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os v&#225;rios estudos mostram que existe uma elevada percentagem de doentes que n&#227;o atingem o controlo efetivo dos fatores de risco cardiovascular &#40;CV&#41;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">8</span></a>&#46; Em Portugal&#44; o estudo DYSIS &#40;<span class="elsevierStyleItalic">Dyslipidemia International Study</span>&#8208;Portugal&#41; mostrou que 63&#37; dos portugueses n&#227;o atingem os valores recomendados de c&#8208;LDL<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">9</span></a>&#46; Existem m&#250;ltiplos fatores respons&#225;veis por este mau controlo dos valores de c&#8208;LDL que s&#227;o dependentes do doente &#40;como a m&#225; ader&#234;ncia e a n&#227;o persist&#234;ncia com a terap&#234;utica&#41;&#44; do m&#233;dico &#40;em especial a in&#233;rcia cl&#237;nica&#41;&#44; e da terap&#234;utica &#40;designadamente a variabilidade interindividual e a efic&#225;cia limitada da terap&#234;utica hipolipemiante&#41;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">5&#44;10</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Nos &#250;ltimos anos&#44; os f&#225;rmacos inibidores da PCSK9 &#40;iPCSK9&#41; surgiram como uma nova op&#231;&#227;o terap&#234;utica que permite uma redu&#231;&#227;o significativa e consistente dos valores de c&#8208;LDL &#40;&#8764;50&#8208;60&#37;&#41; que&#44; por sua vez&#44; se traduziu em v&#225;rios ensaios cl&#237;nicos numa redu&#231;&#227;o adicional do risco de eventos cardiovasculares<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">11&#8211;13</span></a>&#46; Contudo&#44; a terap&#234;utica com iPCSK9 tem custos elevados&#44; pelo que a sua utiliza&#231;&#227;o cl&#237;nica deve ser criteriosa&#44; tendo em considera&#231;&#227;o os dados de custo&#8208;efetividade destes f&#225;rmacos e a manuten&#231;&#227;o da sustentabilidade do sistema de sa&#250;de<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">14</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Este documento baseado no consenso entre autores de v&#225;rias especialidades m&#233;dicas &#40;Cardiologia&#44; Endocrinologia e Medicina Interna&#41; e apoiado por v&#225;rias sociedades cient&#237;ficas&#44; tem como objetivo resumir os principais dados sobre a utiliza&#231;&#227;o cl&#237;nica dos iPCSK9 e estabelecer recomenda&#231;&#245;es&#44; adaptadas &#224; realidade portuguesa&#44; sobre o perfil de doentes que mais pode beneficiar desta terap&#234;utica&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Evid&#234;ncias para a hip&#243;tese do c&#8208;ldl&#58; ser&#225; <span class="elsevierStyleItalic">the lower&#44; the better</span>&#63;</span><p id="par0030" class="elsevierStylePara elsevierViewall">A associa&#231;&#227;o entre o c&#8208;LDL e o desenvolvimento de aterosclerose foi estabelecida h&#225; v&#225;rias d&#233;cadas&#44; a partir de m&#250;ltiplos estudos epidemiol&#243;gicos que mostraram uma rela&#231;&#227;o cont&#237;nua e linear entre a magnitude de exposi&#231;&#227;o a valores plasm&#225;ticos elevados de c&#8208;LDL e o risco de eventos cardiovasculares<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Mais recentemente&#44; dados de v&#225;rios estudos gen&#233;ticos&#44; mais especificamente dos estudos de &#171;aleatoriza&#231;&#227;o Mendeliana&#187;&#44; mostraram mais uma vez de forma consistente que as variantes de v&#225;rios genes que determinam valores mais elevados de c&#8208;LDL se associam a aumento do risco de eventos vasculares<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">16&#44;17</span></a>&#44; confirmando que os n&#237;veis de c&#8208;LDL t&#234;m um papel causal no desenvolvimento de DCV<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Contudo&#44; a evid&#234;ncia cl&#237;nica mais significativa do papel do c&#8208;LDL como fator causal de DCV vem dos ensaios cl&#237;nicos aleatorizados que demonstraram uma rela&#231;&#227;o proporcional entre a magnitude de redu&#231;&#227;o do c&#8208;LDL e a redu&#231;&#227;o do risco de eventos&#46; Uma meta&#8208;an&#225;lise de 36 ensaios envolvendo 170 000 indiv&#237;duos tratados com estatina demonstrou uma redu&#231;&#227;o linear de 22&#37; de risco de eventos CV <span class="elsevierStyleItalic">major</span> por cada mmol&#47;l &#40;39<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; de redu&#231;&#227;o de c&#8208;LDL&#44; estabelecendo o conceito de quanto mais baixo melhor<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">3&#44;18&#44;19</span></a>&#46; Esse benef&#237;cio da terap&#234;utica hipolipemiante &#233; menor no primeiro ano de tratamento &#40;&#8764;10&#37; redu&#231;&#227;o de risco&#41;&#44; seguido de uma redu&#231;&#227;o consistente nos anos seguintes&#44; de 22&#8208;24&#37; por mmol&#47;l reduzido<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">20&#44;21</span></a>&#46; A redu&#231;&#227;o de eventos est&#225; comprovada para diferentes op&#231;&#245;es terap&#234;uticas que em comum t&#234;m o efeito na redu&#231;&#227;o de c&#8208;LDL e aumento da express&#227;o do recetor LDL no hepat&#243;cito &#40;estatina&#44; ezetimiba&#44; resinas&#44; inibidor da PCSK9&#44; cirurgia de <span class="elsevierStyleItalic">bypass</span>&#8208;ileal&#41;&#44; como prova uma meta&#8208;an&#225;lise de 49 estudos&#44; incluindo 312 175 doentes e 39 645 eventos<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">4</span></a>&#46; Finalmente&#44; os ensaios cl&#237;nicos que avaliaram a progress&#227;o da placa de aterosclerose atrav&#233;s ecografia intracoron&#225;ria &#40;IVUS&#41; demonstraram que &#233; poss&#237;vel parar a progress&#227;o da placa de aterosclerose quando se atingem n&#237;veis de c&#8208;LDL inferiores a 70<span class="elsevierStyleHsp" style=""></span>mg&#47;dl<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">22&#44;23</span></a>&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Inibi&#231;&#227;o da PCSK9&#58; do mecanismo de a&#231;&#227;o&#44; aos ensaios cl&#237;nicos de redu&#231;&#227;o de eventos cardiovasculares</span><p id="par0045" class="elsevierStylePara elsevierViewall">A pr&#243;&#8208;prote&#237;na convertase subtilisina quexina tipo 9 &#40;PCSK9&#41; &#233; uma protease da serina que reduz os n&#237;veis de recetores celulares das lipoprote&#237;nas de baixa densidade &#40;r&#8208;LDL&#41;&#46; Desta forma&#44; a sua inibi&#231;&#227;o permite um aumento do n&#250;mero de r&#8208;LDL na superf&#237;cie do hepat&#243;cito o que permite uma diminui&#231;&#227;o dos n&#237;veis s&#233;ricos de c&#8208;LDL &#40;<a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">24</span></a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">No hepat&#243;cito a SREP&#8208;2 regula a transcri&#231;&#227;o de v&#225;rios l&#237;pidos e prote&#237;nas&#44; nomeadamente o recetor do LDL &#40;LDLR&#41; e a pr&#243;&#8208;prote&#237;na convertase subtilisina quexina tipo 9 &#40;PCSK9&#41;&#46; Numa primeira fase a PCSK9 &#233; transformada no reticulo endoplasm&#225;tico na sua forma madura &#40;passo 2&#41; e passa pelo aparelho de Golgi antes de ser secretada &#40;passo 3&#41;&#46; Na superf&#237;cie do hepat&#243;cito o recetor do LDL &#40;LDL&#8208;R&#41; liga&#8208;se ao c&#8208;LDL circulante e este complexo &#233; internalizado para os endossomas no interior do hepat&#243;cito &#40;passo 4&#41;&#46; Em seguida o LDL&#8208;R recircula para a superf&#237;cie do hepat&#243;cito &#40;passo 5&#41;&#44; processo que ocorre cerca de 150 vezes e que permite que mais c&#8208;LDL seja removido da circula&#231;&#227;o&#46; A PCSK9 regula a quantidade de recetores de LDL na superf&#237;cie do hepat&#243;cito&#44; uma vez que quando se liga a este recetor causa a sua internaliza&#231;&#227;o e destrui&#231;&#227;o no lisossoma &#40;passos 6 e 7&#41;&#44; impedindo o LDL&#8208;R de recircular para a superf&#237;cie do hepat&#243;cito&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Os inibidores da PCSK9 s&#227;o anticorpos monoclonais que se ligam &#224; PCSK9 impedindo&#8208;a de se ligar ao recetor do LDL&#44; aumentando assim a quantidade de recetores de LDL na superf&#237;cie do hepat&#243;cito o que permite uma redu&#231;&#227;o significativa dos valores circulantes de c&#8208;LDL<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">25</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">O gene que codifica a PCSK9 foi identificado h&#225; cerca de 15 anos em conex&#227;o com o fen&#243;tipo de hipercolesterolemia familiar&#44; que rapidamente se demonstrou estar associado a uma muta&#231;&#227;o com ganho de fun&#231;&#227;o<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">26&#44;27</span></a>&#46; A identifica&#231;&#227;o subsequente de variantes do PCSK9 com perda de fun&#231;&#227;o&#44; associadas a n&#237;veis de c&#8208;LDL s&#233;rico baixos e menor risco de DCV criou o modelo farmacol&#243;gico para o aparecimento dos inibidores da PCSK9<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">28</span></a>&#46; Rapidamente se desenvolveram anticorpos monoclonais &#40;mAb&#41; contra a PCSK9&#44; dando origem a programas abrangentes de investiga&#231;&#227;o cl&#237;nica para testar a efic&#225;cia cl&#237;nica dos iPCSK9 na redu&#231;&#227;o de eventos cardiovasculares<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">29</span></a>&#46; Em paralelo&#44; continuam a ser desenvolvidas outras formas alternativas de inibi&#231;&#227;o do PCSK9 conforme detalhado na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a><a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">30&#44;31</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Anticorpos monoclonais anti&#8208;PCSK9 &#40;IPCSK9&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Os anticorpos monoclonais ligam&#8208;se &#224; PCSK9 impedindo a sua fixa&#231;&#227;o ao r&#8208;LDL e a consequente degrada&#231;&#227;o no lisossoma&#44; aumentando o n&#250;mero de recetores de LDL &#40;<a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">25</span></a>&#46; Foram desenvolvidos tr&#234;s anticorpos&#58; o alirocumab&#44; o bococizumab e o evolocumab&#46; O alirocumab e o evolocumab s&#227;o imunoglobulinas totalmente humanas&#44; dos isotipos G1 e G2&#44; respetivamente&#46; Por outro lado&#44; o bococizumab &#233; um anticorpo monoclonal humanizado do isotipo G2&#46; Todos s&#227;o administrados por via subcut&#226;nea e&#44; como s&#227;o anticorpos completos&#44; apresentam uma semivida longa&#44; compat&#237;vel com uma administra&#231;&#227;o em cada 2 a 4 semanas&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Efeito no perfil lip&#237;dico</span><p id="par0070" class="elsevierStylePara elsevierViewall">Ap&#243;s a administra&#231;&#227;o subcut&#226;nea &#40;SC&#41; de 140&#8208;420<span class="elsevierStyleHsp" style=""></span>mg de evolocumab&#44; o pico mediano das concentra&#231;&#245;es s&#233;ricas &#233; alcan&#231;ado em tr&#234;s&#8208;quatro dias&#46; A biodisponibilidade absoluta &#233; de 72&#37; e a semivida &#40;t&#189;&#41; efetiva de 11&#8208;17 dias&#46; A administra&#231;&#227;o SC continuada determina um aumento de exposi&#231;&#227;o ao f&#225;rmaco proporcional &#224; dose&#44; alcan&#231;ando um estado de equil&#237;brio das concentra&#231;&#245;es s&#233;ricas m&#237;nimas &#224;s 12 semanas&#46; A administra&#231;&#227;o &#250;nica SC de evolocumab determina a supress&#227;o m&#225;xima precoce&#44; quase completa&#44; &#224;s quatro horas da PCSK9 livre circulante&#44; com um nadir m&#233;dio na redu&#231;&#227;o do LDL&#8208;C em 14&#8208;21 dias&#46; As varia&#231;&#245;es da PCSK9 livre e das lipoprote&#237;nas s&#233;ricas s&#227;o revers&#237;veis&#44; ap&#243;s a descontinua&#231;&#227;o do tratamento&#44; sem qualquer evid&#234;ncia de efeito de retoma &#40;<span class="elsevierStyleItalic">rebound</span>&#41;&#46; As caracter&#237;sticas farmacocin&#233;ticas do alirocumab s&#227;o compar&#225;veis&#46; Ap&#243;s a administra&#231;&#227;o SC&#44; os tempos m&#233;dios para a concentra&#231;&#227;o s&#233;rica m&#225;xima &#40;tmax&#41; s&#227;o tr&#234;s&#8208;sete dias&#44; a sua biodisponibilidade absoluta &#233; &#8776; 85&#37; e o estado estacion&#225;rio &#233; obtido ap&#243;s 2&#8208;3 doses&#46; A semivida m&#233;dia aparente &#233; de 17&#8208;20 dias<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">32&#44;33</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Os anticorpos monoclonais anti&#8208;PCSK9 reduzem os n&#237;veis de C&#8208;LDL em cerca de 60&#37;&#44; conforme demonstrado em v&#225;rios estudos de curta dura&#231;&#227;o &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">34&#44;35</span></a>&#44; independentemente da terap&#234;utica antidislipid&#233;mica de base<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">36</span></a>&#46; Contudo&#44; a efic&#225;cia &#233; ligeiramente maior nos doentes medicados com estatina devido ao aumento da express&#227;o do gene do PCSK9<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">37</span></a>&#46; Al&#233;m da redu&#231;&#227;o do c&#8208;LDL&#44; esta classe permite uma redu&#231;&#227;o do colesterol total de cerca de 38&#37;&#44; da apolipoprote&#237;na B &#40;ApoB&#41; de 50&#37; e a da lipoprote&#237;na &#40;a&#41; &#91;Lp&#40;a&#41;&#93; de 28&#37;&#46; Tamb&#233;m em doentes intolerantes &#224;s estatinas a sua utiliza&#231;&#227;o permitiu uma redu&#231;&#227;o do c&#8208;LDL de 51&#44;4&#37;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">38&#8211;41</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">A longo prazo&#44; a efic&#225;cia na redu&#231;&#227;o do c&#8208;LDL manteve&#8208;se para o alirocumab &#40;&#8208;54&#44;7&#37; aos 48 meses&#41; e para o evolocumab &#40;&#8208;54&#44;0&#37; aos 39 meses&#41; nos ensaios de eventos CV<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">11&#44;13</span></a>&#46; Contudo&#44; em rela&#231;&#227;o ao bococizumab &#8208; que &#233; um anticorpo humanizado da PCSK9 &#8208; observou&#8208;se uma atenua&#231;&#227;o da sua efic&#225;cia &#40;&#8208;38&#44;3&#37; aos 24 meses&#41;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a>&#44; geralmente atribu&#237;da ao desenvolvimento de anticorpos neutralizantes do bococizumab&#44; efeito que ocorre em cerca de 30&#37; dos doentes ao fim de um ano&#44; o que levou &#224; interrup&#231;&#227;o do seu programa de desenvolvimento cl&#237;nico<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">35</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">De acordo com a sua farmacodin&#226;mica&#44; os anticorpos monoclonais anti&#8208;PCSK9 s&#227;o eficazes na redu&#231;&#227;o do c&#8208;LDL em todos os doentes que sejam capazes de expor r&#8208;LDL hep&#225;ticos&#46; Nos v&#225;rios estudos realizados em doentes com hipercolesterolemia familiar heterozig&#243;tica &#40;HeHF&#41; sob estatina&#44; com ou sem ezetimiba&#44; os anticorpos monoclonais anti&#8208;PCSK9 reduziram significativamente os valores de c&#8208;LDL &#40;entre 39&#44;1&#37; e 61&#44;3&#37;&#41;&#44; independentemente do tipo de muta&#231;&#227;o do r&#8208;LDL<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">42</span></a>&#46; Na HF homozig&#243;tica &#40;HoHF&#41;&#44; a efic&#225;cia do evolocumab na redu&#231;&#227;o do c&#8208;LDL foi muito vari&#225;vel&#44; observando&#8208;se varia&#231;&#245;es percentuais de 22&#44;9&#37; a 40&#44;8&#37; nos doentes com pelo menos um alelo com muta&#231;&#227;o defeituosa no gene r&#8208;LDL<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">42&#8211;44</span></a>&#46; Os doentes com HoHF&#44; com d&#233;fice duplo do r&#8208;LDL&#44; naturalmente&#44; respondem de forma muito deficiente ao tratamento&#46; T&#234;m sido descritos casos raros de aus&#234;ncia de resposta ou de resposta atenuada aos iPCSK9&#46; A variabilidade de resposta est&#225; presente na hipercolesterolemia autoss&#243;mica recessiva &#40;por muta&#231;&#227;o da prote&#237;na adaptadora do recetor de LDL tipo 1 &#8208; LDLRAP1 &#8211; que participa na internaliza&#231;&#227;o do complexo r&#8208;LDLR&#47;c&#8208;LDL no hepat&#243;cito e&#44; consequentemente determina um aumento do c&#8208;LDL&#41; ou na muta&#231;&#227;o R410S do r&#8208;LDL que leva tamb&#233;m a uma altera&#231;&#227;o no metabolismo do r&#8208;LDL nos endossomas&#46; A avalia&#231;&#227;o gen&#233;tica poder&#225; estar assim indicada nos doentes n&#227;o respondedores aos iPCSK9&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">De notar ainda que esta classe terap&#234;utica n&#227;o reduziu os valores de prote&#237;na C&#8208;reativa&#44; o que pode sugerir que o impacto das estatinas neste biomarcador seja um efeito pleiotr&#243;pico independente da redu&#231;&#227;o do c&#8208;LDL<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">45&#44;46</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Estudos de eventos cardiovasculares</span><p id="par0095" class="elsevierStylePara elsevierViewall">Os anticorpos monoclonais anti&#8208;PCSK9 foram avaliados em quatro ensaios cl&#237;nicos de eventos CV aleatorizados e controlados com placebo&#44; que inclu&#237;ram mais de 70 mil doentes&#44; maioritariamente em preven&#231;&#227;o secund&#225;ria conforme detalhado na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a><a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">11&#8211;13</span></a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">O ensaio cl&#237;nico FOURIER&#44; que testou a utiliza&#231;&#227;o do evolucumab&#44; numa popula&#231;&#227;o de doentes est&#225;veis&#44; mas com doen&#231;a vascular estabelecida&#44; foi o primeiro a demonstrar a redu&#231;&#227;o de eventos CV com os IPCSK9 numa popula&#231;&#227;o de 27 564 doentes em preven&#231;&#227;o secund&#225;ria &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">11</span></a>&#46; Neste estudo o evolocumab reduziu significativamente o risco relativo do resultado prim&#225;rio combinado de morte CV&#44; enfarte do mioc&#225;rdio &#40;EM&#41;&#44; acidente vascular cerebral &#40;AVC&#41;&#44; internamento por angina inst&#225;vel &#40;AI&#41; ou revasculariza&#231;&#227;o coron&#225;ria &#40;RC&#41; em 15&#37;&#46; Observaram&#8208;se redu&#231;&#245;es significativas no risco relativo de EM &#40;27&#37;&#41;&#44; AVC &#40;21&#37;&#41; e RC &#40;22&#37;&#41;&#46; O evolocumab n&#227;o reduziu o risco de morte CV e de AI&#46; Os resultados foram consistentes independentemente do c&#8208;LDL basal e da terap&#234;utica anti&#8208;dislipid&#233;mica de base&#46; O efeito do evolocumab nos eventos CV foi mais acentuado depois do primeiro ano de tratamento&#44; traduzido numa redu&#231;&#227;o de 19&#37; no risco relativo do resultado prim&#225;rio e de 25&#37; no resultado secund&#225;rio principal em compara&#231;&#227;o com o placebo&#44; tal como foi observado nos ensaios cl&#237;nicos com estatinas<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">18</span></a>&#46; A magnitude da redu&#231;&#227;o do risco relativo de eventos CV com o evolocumab por unidade de redu&#231;&#227;o do c&#8208;LDL &#40;mmol&#47;l&#41; foi sobrepon&#237;vel &#224; descrita na an&#225;lise do <span class="elsevierStyleItalic">Cholesterol Treatment Trialists Collaboration</span> &#40;CTTC&#41;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">3</span></a>&#46; Na an&#225;lise por redu&#231;&#227;o do risco absoluto do resultado prim&#225;rio e do secund&#225;rio principal o benef&#237;cio foi mais acentuado nos doentes de risco mais elevado&#46; Efetivamente&#44; observaram&#8208;se valores do n&#250;mero necess&#225;rio tratar &#40;NNT&#41; mais baixos nos indiv&#237;duos com doen&#231;a multivaso&#44; EM recorrente ou EM h&#225; menos de dois anos &#40;NNT 34 e 40&#44; respetivamente&#41;&#44; com doen&#231;a arterial perif&#233;rica &#40;NNT 29 para os dois resultados cl&#237;nicos&#41; ou com &#237;ndice de risco TIMI 2<span class="elsevierStyleSup">o</span>P superior a 4 pontos &#40;NNT 28&#41; em compara&#231;&#227;o com os verificados na popula&#231;&#227;o total &#40;NNT 67 para os dois resultados cl&#237;nicos&#41;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">36&#44;47&#44;48</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Os ensaios SPIRE&#8208;1 e SPIRE&#8208;2 testaram o efeito do bococizumab um total de 27 438 doentes maioritariamente em preven&#231;&#227;o secund&#225;ria&#44; tendo o SPIRE&#8208;2 um limiar de elegibilidade para o c&#8208;LDL e c&#8208;n&#227;oHDL mais elevado &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a>&#46; Os dois estudos foram terminados precocemente por atenua&#231;&#227;o da efic&#225;cia hipolipemiante do bococizumab ao longo do tempo&#46; Ainda assim&#44; o bococizumab reduziu o risco relativo do resultado prim&#225;rio combinado de morte CV&#44; EM&#44; AVC ou AI com necessidade de revasculariza&#231;&#227;o urgente em 12&#37; e o resultado secund&#225;rio combinado de morte CV&#44; EM ou AVC em 13&#37;&#44; embora as diferen&#231;as n&#227;o tenham sido estatisticamente significativas&#46; No SPIRE 2&#44; em que a exposi&#231;&#227;o ao bococizumab foi mais prolongada e o c&#8208;LDL basal mais elevado&#44; observaram&#8208;se redu&#231;&#245;es estatisticamente significativas no risco relativo do resultado prim&#225;rio &#40;21&#37;&#41; e do secund&#225;rio &#40;26&#37;&#41;&#44; em compara&#231;&#227;o com o placebo&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Finalmente&#44; o ensaio cl&#237;nico ODISSEY&#8208;Outcomes incluiu 18 924 doentes com s&#237;ndroma coron&#225;ria aguda recente&#44; seguidos durante uma mediana de 2&#44;6 anos&#44; sob terap&#234;utica com estatina &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">13</span></a>&#46; O alirocumab reduziu significativamente o risco relativo do resultado prim&#225;rio combinado de morte de causa coron&#225;ria&#44; EM&#44; AVC ou AI em 15&#37; e do resultado secund&#225;rio combinado de morte de qualquer causa&#44; EM ou AVC em 14&#37;&#46; Ocorreram redu&#231;&#245;es significativas no risco relativo de EM n&#227;o fatal &#40;14&#37;&#41;&#44; AVC &#40;27&#37;&#41;&#44; AI &#40;39&#37;&#41; e RC &#40;12&#37;&#41;&#46; O alirocumab n&#227;o reduziu o risco de morte coron&#225;ria ou CV&#46; O benef&#237;cio foi consistente nas an&#225;lises de subgrupos&#46; Numa an&#225;lise <span class="elsevierStyleItalic">post hoc</span> observou&#8208;se uma redu&#231;&#227;o significativa de 28&#37; no risco relativo da morte coron&#225;ria e de 31&#37; na morte CV com o alirocumab <span class="elsevierStyleItalic">versus</span> placebo&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Em resumo&#44; no seu conjunto&#44; os estudos de eventos cardiovasculares com os anticorpos monoclonais anti&#8208;PCSK9 corroboram o conceito estabelecido da associa&#231;&#227;o linear entre o c&#8208;LDL obtido e a taxa de eventos CV&#44; independentemente do valor de LDL atingido&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Utiliza&#231;&#227;o de IPCSK9 na hipercolesterolemia familiar</span><p id="par0120" class="elsevierStylePara elsevierViewall">A hipercolesterolemia familiar associa&#8208;se a um risco acrescido de doen&#231;a cardiovascular numa fase prematura<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">49</span></a>&#46; &#201; sabido que indiv&#237;duos com valores c&#8208;LDL&#62;190<span class="elsevierStyleHsp" style=""></span>mg&#47;dL s&#227;o considerados de risco cardiovascular elevado<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">5</span></a> e que a sua maioria tem hipercolesterolemia familiar &#40;HF&#41;&#44; seja monog&#233;nica &#40;causada por muta&#231;&#245;es de genes envolvidos no metabolismo do c&#8208;LDL&#41; ou polig&#233;nica &#40;resultante da intera&#231;&#227;o de dieta aterog&#233;nica e m&#250;ltiplos fatores gen&#233;ticos mal definidos&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A popula&#231;&#227;o com HF &#233; bastante heterog&#233;nea devido ao n&#250;mero elevado de poss&#237;veis muta&#231;&#245;es causadoras de HF&#44; sendo que a extens&#227;o da doen&#231;a ateroscler&#243;tica e o risco cardiovascular dependem fundamentalmente dos n&#237;veis de c&#8208;LDL e do tempo de exposi&#231;&#227;o&#46; A causa mais frequente de hipercolesterolemia familiar monog&#233;nica &#233; a muta&#231;&#227;o do gene do r&#8208;LDL &#40;&#8764;90&#37;&#41;&#44; seguida de muta&#231;&#245;es do gene ApoB &#40;&#8764;5&#37;&#41;&#44; muta&#231;&#245;es com ganho de fun&#231;&#227;o do gene PCSK9 &#40;&#60;1&#37;&#41; e muito raramente muta&#231;&#245;es com perda de fun&#231;&#227;o do gene LDLRAP1 &#40;que codifica uma prote&#237;na que promove a internaliza&#231;&#227;o do complexo r&#8208;LDLR&#47;c&#8208;LDL&#41;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">50</span></a>&#46; A forma heterozig&#243;tica de HF &#40;HFHe&#41; tem uma preval&#234;ncia estimada de 1&#47;500 &#8208; 1&#47;200 na popula&#231;&#227;o geral sendo a forma homozig&#243;tica &#40;HFHo&#41; mais rara&#58; &#8764;1&#47;160 000 &#8208; 1&#47;300 000<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">42</span></a>&#46; A HF est&#225; subdiagnosticada particularmente a forma heterozig&#243;tica em que muitas vezes a suspeita s&#243; surge ap&#243;s um evento coron&#225;rio precoce &#40;idade &#60; 55 anos nos homens e &#60; 60 anos nas mulheres&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Tamb&#233;m na dislipidemia familiar a redu&#231;&#227;o dos valores de c&#8208;LDL reduz o risco de eventos CV&#46; Nestes doentes&#44; a preven&#231;&#227;o prim&#225;ria &#233; mais eficaz do que a preven&#231;&#227;o secund&#225;ria na redu&#231;&#227;o da mortalidade por doen&#231;a coron&#225;ria &#40;48&#37; <span class="elsevierStyleItalic">versus</span> 25&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">51</span></a>&#46; Em geral&#44; na dislipidemia familiar recomenda&#8208;se que o tratamento farmacol&#243;gico se dever&#225; iniciar o mais precocemente poss&#237;vel &#40;a partir dos 8&#8208;10 anos de idade&#41; para prevenir excesso de mortalidade em adultos&#46; Al&#233;m disso&#44; ultimamente tem&#8208;se debatido a estratifica&#231;&#227;o de risco CV dos doentes com HF&#44; numa tentativa de identificar precocemente os doentes de risco mais elevado&#44; em que se justifica uma terap&#234;utica hipolipemiante mais agressiva&#46; De acordo com as recomenda&#231;&#245;es europeias nos indiv&#237;duos adultos com HF&#44; sem doen&#231;a cardiovascular estabelecida&#44; o valor alvo de c&#8208;LDL deve ser &#60;100<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<span class="elsevierStyleSup">5</span>&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Os IPCSK9 foram testados em v&#225;rios estudos em indiv&#237;duos com HF&#46; O programa PROFICIO &#40;evolocumab&#41; incluiu doentes com HFHe &#40;RUTHERFORD&#8208;2&#41; e HFHo &#40;TESLA&#8208;A&#44;TESLA&#8208;B&#41;&#44; e est&#225; em curso o estudo TAUSSIG&#46; O programa ODYSSEY &#40;alirocumab&#41; incluiu apenas doentes com HFHe&#44; conforme detalhado na <a class="elsevierStyleCrossRef" href="#tbl0030">tabela 4</a><a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">42</span></a>&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">Estes estudos demonstraram a efic&#225;cia dos IPCSK9&#44; particularmente na HFHe&#44; permitindo redu&#231;&#227;o adicional de c&#8208;LDL &#8764;60&#37; em doentes com terap&#234;utica hipolipemiante m&#225;xima&#44; o que permite que 80&#37; destes doentes consiga atingir o valor alvo de c&#8208;LDL&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Outras formas de inibi&#231;&#227;o da PCSK9</span><p id="par0145" class="elsevierStylePara elsevierViewall">A terap&#234;utica com oligonucle&#243;tideos&#44; mol&#233;culas de cadeia simples ou dupla de DNA ou RNA com 10&#8208;50 nucleot&#237;deos&#44; an&#225;logos sint&#233;ticos de &#225;cidos nucleicos naturais&#44; &#233; um conceito emergente no tratamento das doen&#231;as cardiovasculares e do metabolismo lip&#237;dico&#46; Habitualmente&#44; este tipo de terap&#234;utica divide&#8208;se em dois grupos&#44; um&#44; constitu&#237;do pelos oligonucle&#243;tidos antisentido &#40;ASO&#41;&#44; as ribozimas e as pequenas mol&#233;culas de &#225;cido ribonucleico de interfer&#234;ncia &#40;siRNA&#44; que suprimem a express&#227;o de uma prote&#237;na por hibrida&#231;&#227;o com o ARN mensageiro alvo&#41; e um segundo grupo constitu&#237;do por apt&#226;meros que se ligam como anticorpos &#224;s prote&#237;nas alvo&#44; inibindo a sua fun&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">59</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">O inclisiran&#44; uma pequena cadeia &#250;nica de &#225;cido ribonucleico de interfer&#234;ncia&#44; &#233; a alternativa aos anticorpos monoclonais que se encontra em fase mais avan&#231;ada de desenvolvimento cl&#237;nico&#46; Este agente sint&#233;tico possui uma formula&#231;&#227;o com um ligando de N&#8208;acetilgalactosamina que permite a sua capta&#231;&#227;o hep&#225;tica&#44; e atua sinalizando o RNA mensageiro do PCSK9 para ser clivado o que condiciona a diminui&#231;&#227;o da sua s&#237;ntese<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">60</span></a>&#46; O efeito farmacodin&#226;mico &#233; prolongado o que permite a sua administra&#231;&#227;o parent&#233;rica semestral&#46; No estudo de fase II ORION&#8208;1&#44; a dose de 300<span class="elsevierStyleHsp" style=""></span>mg administrada por via subcut&#226;nea no in&#237;cio do estudo e aos tr&#234;s meses reduziu o C&#8208;LDL em 52&#44;6&#37;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">61</span></a>&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Seguran&#231;a dos anticorpos monoclonais da PCSK9</span><p id="par0155" class="elsevierStylePara elsevierViewall">No geral&#44; a utiliza&#231;&#227;o dos anticorpos monoclonais anti&#8208;PCSK9 revelou&#8208;se bastante segura nos estudos de eventos cardiovasculares &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 5</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">11&#8211;13</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">tabela 6</a>&#41;&#44; confirmando os dados dos estudos iniciais<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">36</span></a>&#46; A administra&#231;&#227;o destes agentes pode originar uma rea&#231;&#227;o local como eritema&#44; tumefa&#231;&#227;o ou prurido&#44; geralmente ligeira&#44; cuja incid&#234;ncia variou entre 2&#44;1&#37; e 10&#44;4&#37; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 5</a>&#41;&#46; Este valor mais elevado foi observado com o bococizumab e pode estar associado &#224; sua natureza parcialmente murina&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">N&#227;o se observou um aumento da incid&#234;ncia do diagn&#243;stico de diabetes <span class="elsevierStyleItalic">mellitus</span> de novo &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 5</a>&#41;&#44; contrariando a hip&#243;tese de que valores mais baixos de C&#8208;LDL poderem condicionar maior risco de diabetes<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">62</span></a>&#46; Este efeito neutro sobre o controlo glic&#233;mico foi confirmado numa suban&#225;lise do estudo FOURIER<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">63</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Tamb&#233;m n&#227;o se observou toxicidade hep&#225;tica ou muscular&#46; O desenvolvimento de anticorpos neutralizantes do dos mAb anti&#8208;PCSK9 foi descrito em 43 doentes sob alirocumab &#40;0&#44;5&#37;&#41; no ODISSEY&#8208;Outcomes mas n&#227;o foi documentado para o evolocumab no FOURIER&#46; Como j&#225; foi referido&#44; a dete&#231;&#227;o frequente de anticorpos neutralizantes para o bococizumab levou &#224; interrup&#231;&#227;o do seu programa de desenvolvimento cl&#237;nico&#46; As rea&#231;&#245;es adversas mais frequentes com o evolocumab foram a nasofaringite &#40;4&#44;8&#37;&#41; e infe&#231;&#227;o das vias respirat&#243;rias superiores &#40;3&#44;2&#37;&#41;&#44; a dorsalgia &#40;3&#44;1&#37;&#41; e a artralgia &#40;2&#44;2&#37;&#41;&#44; as s&#237;ndromes gripais &#40;2&#44;3&#37;&#41; e as n&#225;useas &#40;2&#44;1&#37;&#41;&#46; Com o alirocumab&#44; as rea&#231;&#245;es adversas mais frequentes foram as rea&#231;&#245;es locais no local da inje&#231;&#227;o &#40;<span class="elsevierStyleItalic">e&#46;g&#46;</span> eritema&#44; dor e hematoma no local da inje&#231;&#227;o&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Finalmente&#44; os receios de que valores muito baixos de c&#8208;LDL pudessem estar relacionados com disfun&#231;&#227;o cognitiva n&#227;o foram&#44; at&#233; &#224; data&#44; confirmados nos ensaios cl&#237;nicos&#46; No estudo EBBINGHAUS que avaliou espec&#237;fica e detalhadamente o desempenho neurocognitivo dos doentes sob evolocumab&#44; este foi sobrepon&#237;vel ao do placebo nas avalia&#231;&#245;es &#224;s 24 semanas e no final do ensaio cl&#237;nico<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">64</span></a>&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Apesar da excelente seguran&#231;a demonstrada pelos anticorpos monoclonais anti&#8208;PCSK9 a m&#233;dio prazo&#44; n&#227;o se conhecem os efeitos da exposi&#231;&#227;o prolongada a estes agentes&#46; As s&#237;ndromas gen&#233;ticas associadas &#224; hipocolesterolemia familiar&#44; em particular as originadas por muta&#231;&#245;es do PCSK9 com perda de fun&#231;&#227;o&#44; podem representar um modelo de exposi&#231;&#227;o prolongada aos anti&#8208;PCSK9<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">65</span></a>&#46; Nos portadores destas doen&#231;as n&#227;o est&#227;o descritos dist&#250;rbios neurocognitivos&#44; exceto numa muta&#231;&#227;o espec&#237;fica da ApoB &#40;isoforma truncada de ApoB29&#46;4&#41;&#46; Contudo&#44; o risco de esteatose hep&#225;tica &#233; elevado&#44; sendo superior a 70&#37; nos portadores de isoformas truncadas de ApoB100&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">An&#225;lises de custo&#8208;efetividade dos IPCSK9</span><p id="par0180" class="elsevierStylePara elsevierViewall">Apesar da efic&#225;cia dos IPCSK9 na redu&#231;&#227;o do risco de eventos cardiovasculares&#44; a sua utiliza&#231;&#227;o na pr&#225;tica cl&#237;nica tem sido relativamente baixa<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">66</span></a>&#44; sobretudo devido ao pre&#231;o do tratamento&#46; Mais do que o pre&#231;o&#44; hoje em dia &#233; essencial a avalia&#231;&#227;o da custo&#8208;efetividade da terap&#234;utica&#46; Em rela&#231;&#227;o aos IPCSK9&#44; existem v&#225;rios estudos de custo&#8208;efetividade publicados&#46; Os resultados destas an&#225;lises t&#234;m sido muito heterog&#233;neos&#44; com valores de ICER &#40;<span class="elsevierStyleItalic">incremental cost&#8208;effectiveness ratio</span>&#41; que variam entre os 30&#46;000&#8364; e os 166&#46;000&#8364; por QALY ganho<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">67</span></a> dependendo dos modelos de simula&#231;&#227;o&#44; do perfil de doentes inclu&#237;dos na an&#225;lise&#44; do contexto de utiliza&#231;&#227;o e do custo do tratamento&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Para melhorar a custo&#8208;efetividade destes f&#225;rmacos tem sido proposta uma estrat&#233;gia de &#171;m&#225;ximo risco&#47;m&#225;ximo benef&#237;cio&#187;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">68</span></a>&#46; Isto significa que a utiliza&#231;&#227;o destes f&#225;rmacos deve ser privilegiada nos doentes de &#171;m&#225;ximo risco&#187;&#44; nomeadamente aqueles com maior probabilidade de virem a ter um evento cardiovascular como aqueles com antecedentes de DCV &#43; atingimento multivascular ou diabetes&#46; Por outro lado&#44; tendo como premissa que a redu&#231;&#227;o do risco relativo em doentes com risco CV elevado &#233; proporcional &#224; diminui&#231;&#227;o absoluta do c&#8208;LDL e que a magnitude da redu&#231;&#227;o percentual de c&#8208;LDL com os IPCSK9 &#233; semelhante nos diferentes subgrupos de c&#8208;LDL basal&#44; os doentes com valores iniciais mais elevados de c&#8208;LDL ir&#227;o alcan&#231;ar a maior redu&#231;&#227;o absoluta no c&#8208;LDL e&#44; consequente&#44; uma redu&#231;&#227;o mais significativa do risco CV &#40;&#171;m&#225;ximo benef&#237;cio&#187;&#41;&#46; &#201; com base neste conceito que&#44; nestas recomenda&#231;&#245;es&#44; prop&#245;e&#8208;se uma utiliza&#231;&#227;o preferencial nos grupos de doentes que mais podem beneficiar da terap&#234;utica atendendo&#44; simultaneamente&#44; ao risco CV do doente e o valor absoluto de c&#8208;LDL&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Relativamente &#224;s an&#225;lises de custo&#8208;efetividade na realidade portuguesa&#44; apesar dos dados n&#227;o serem conhecidos&#44; em 28 de dezembro de 2018&#44; o INFARMED apresentou o Relat&#243;rio P&#250;blico de Avalia&#231;&#227;o Pr&#233;via do Medicamento em Meio Hospitalar respeitante ao evolocumab&#44; que considera que &#171;os valores de custo&#8208;efetividade incrementais associados &#224; introdu&#231;&#227;o do evolucomab no arsenal terap&#234;utico&#44; assim como os resultados do impacto or&#231;amental&#44; foram considerados aceit&#225;veis&#187;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">69</span></a>&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Recomenda&#231;&#245;es para a utiliza&#231;&#227;o dos IPCSK9</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Utiliza&#231;&#227;o dos IiPCSK9 em preven&#231;&#227;o secund&#225;ria</span><p id="par0195" class="elsevierStylePara elsevierViewall">Os doentes com DCV estabelecida e&#44; em particular&#44; os que j&#225; tiveram um evento de natureza aterotromb&#243;tica&#44; s&#227;o aqueles que apresentam maior risco de recorr&#234;ncia de eventos CV<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">70</span></a>&#46; Dada a associa&#231;&#227;o entre os valores de c&#8208;LDL e o risco de eventos&#44; os objetivos terap&#234;uticos recomendados de c&#8208;LDL para estes doentes s&#227;o particularmente restritivos&#44; sendo desej&#225;vel atingir c&#8208;LDL &#60;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dl<span class="elsevierStyleSup">5</span>&#44; mas reconhecendo&#8208;se que h&#225; subgrupos de &#171;risco extremo&#187;&#44; que poder&#227;o beneficiar de valores ainda mais baixos&#44; nomeadamente &#60; 55<span class="elsevierStyleHsp" style=""></span>mg&#47;dl<span class="elsevierStyleSup">7</span>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Nestes doentes&#44; o primeiro passo na terap&#234;utica deve ser a utiliza&#231;&#227;o de estatina de alta intensidade&#44; nomeadamente atorvastatina 40&#8208;80<span class="elsevierStyleHsp" style=""></span>mg ou rosuvastatina 20&#8208;40<span class="elsevierStyleHsp" style=""></span>mg&#44; a que se associa um aconselhamento nutricional adequado e o cumprimento adequado das medidas de estilo de vida&#46; Segundo alguns modelos de simula&#231;&#227;o publicados&#44; estima&#8208;se que 32&#37; dos doentes n&#227;o v&#227;o atingir o valor alvo apenas com estatina de alta intensidade&#44; sendo necess&#225;rio recorrer a associa&#231;&#245;es de antidislipid&#233;micos<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">71</span></a>&#46; Deste modo&#44; o passo seguinte &#233; considerar a associa&#231;&#227;o de ezetimiba que&#44; pelo seu custo e boa tolerabilidade&#44; permite uma redu&#231;&#227;o adicional de c&#8208;LDL<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">72</span></a> e desse modo cerca de mais 19&#37; dos doentes atingir&#227;o o valor de c&#8208;LDL desejado de acordo com a mesma an&#225;lise&#46; Ainda assim&#44; h&#225; cerca de 14&#37; que ir&#227;o manter valores de c&#8208;LDL acima do desej&#225;vel&#44; para os quais dever&#225; ser considerada a terap&#234;utica com IPCSK9&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">A utiliza&#231;&#227;o racional destes f&#225;rmacos passa pela identifica&#231;&#227;o de grupos de maior risco absoluto e com valor de c&#8208;LDL mais elevado&#44; nos quais o benef&#237;cio esperado &#233; maior&#46; Esta tem sido a postura da maioria das recomenda&#231;&#245;es j&#225; publicadas sobre a utiliza&#231;&#227;o dos IPCSK9&#44; conforme detalhado na <a class="elsevierStyleCrossRef" href="#tbl0020">tabela 5</a>&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">O <span class="elsevierStyleItalic">National Institute for Health and Care Excellence</span> &#40;NICE&#41;&#44; em 2016&#44; emitiu recomenda&#231;&#245;es para a sua utiliza&#231;&#227;o em doentes com doen&#231;a cardiovascular estabelecida se os valores de c&#8208;LDL&#62; 150<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e alto risco &#40;SCA&#44; AVC isqu&#233;mico&#44; procedimento de revasculariza&#231;&#227;o coron&#225;ria ou arterial&#44; doen&#231;a coron&#225;ria ou doen&#231;a arterial perif&#233;rica&#41; ou &#62; 130<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e muito alto risco &#40;doen&#231;a polivascular ou eventos CV recorrentes&#41;&#46; O &#250;nico cen&#225;rio em que foi considerada a terap&#234;utica em preven&#231;&#227;o prim&#225;ria foi a com HeHF se c&#8208;LDL &#62; 190<span class="elsevierStyleHsp" style=""></span>mg&#47;dl<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">73</span></a>&#46; A Sociedade Espanhola de Cardiologia &#40;SEC&#41; considera a utiliza&#231;&#227;o destes f&#225;rmacos em doentes em preven&#231;&#227;o secund&#225;ria que tenham cardiopatia isqu&#233;mica e c&#8208;LDL &#62; 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl apesar de tratamento otimizado e em doentes com c&#8208;LDL&#62; 70<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e SCA recorrente ou cardiopatia isqu&#233;mica e hipercolesterolemia familiar<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">74</span></a>&#46; Al&#233;m disso&#44; &#233; recomendada a utiliza&#231;&#227;o de IPCSK9 nos doentes com cardiopatia isqu&#233;mica e intoler&#226;ncia comprovada &#224;s estatinas e ainda nos doentes que apesar de n&#227;o terem doen&#231;a cardiovascular conhecida tenham c&#8208;LDL &#62; 130<span class="elsevierStyleHsp" style=""></span>mg&#47;dL e diabetes &#40;tipo 1 ou 2&#41; com les&#227;o de &#243;rg&#227;o alvo &#40;LOA&#41;&#44; doen&#231;a renal cr&#243;nica &#40;DRC&#41; com TFG &#60; 60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#44;73 m2 ou SCORE&#62; 10&#37;&#46; A <span class="elsevierStyleItalic">Task Force</span> da Sociedade Europeia de Cardiologia &#40;ESC&#41; e a Sociedade Europeia de Aterosclerose &#40;ESA&#41; prop&#245;e como candidatos a esta terap&#234;utica os doentes com muito alto risco cardiovascular&#44; incluindo os doentes com evid&#234;ncia cl&#237;nica ou imagiol&#243;gica de doen&#231;a ateroscler&#243;tica que&#44; apesar de dose m&#225;xima de estatina&#44; e ap&#243;s associa&#231;&#227;o de ezetimiba&#44; t&#234;m c&#8208;LDL &#62; 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dl ou &#62; 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl se evid&#234;ncia de r&#225;pida progress&#227;o da doen&#231;a &#40;definida como recorr&#234;ncia de SCA&#44; revasculariza&#231;&#227;o n&#227;o programada ou AVC nos 5 anos ap&#243;s o evento &#237;ndex&#41;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">75</span></a>&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">As recomenda&#231;&#245;es do consenso de peritos do <span class="elsevierStyleItalic">American College of Cardiology</span> &#40;ACC&#41; sobre o uso de antidislipid&#233;micos que n&#227;o estatinas s&#227;o mais abrangentes&#44; definindo que se deve considerar a associa&#231;&#227;o de ezetimiba ou inibidor PCSK9 na preven&#231;&#227;o secund&#225;ria em doentes com doen&#231;a ateroscler&#243;tica estabelecida se n&#227;o tiver sido atingido o objetivo de redu&#231;&#227;o de &#8805; 50&#37; &#40;considerar c&#8208;LDL&#60; 70<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; sob a dose m&#225;xima tolerada de estatina&#46; Para os doentes sem comorbilidades associadas&#44; a adi&#231;&#227;o de ezetimiba deve ser o primeiro passo&#46; Contudo&#44; nos doentes com um fator multiplicador de risco &#40;como diabetes&#44; doen&#231;a renal cr&#243;nica&#44; evento cardiovascular sob estatina&#44; AVC isqu&#233;mico ou EAM pr&#233;vio&#44; &#8805;65 anos&#41; o inibidor PCSK9 deve ser preferido ao ezetimiba se a redu&#231;&#227;o adicional pretendida for &#62;25&#37;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">76</span></a>&#46; Mais recentemente as recomenda&#231;&#245;es americanas para a abordagem da hipercolesterolemia refor&#231;am o conceito de otimiza&#231;&#227;o terap&#234;utica inicial com ezetimiba antes de considerar o IPCSK9&#44; acrescentando ainda uma nova recomenda&#231;&#227;o de valor relacionada com a an&#225;lise de custo&#8208;efectividade para estes f&#225;rmacos&#44; os quais&#44; para os valores de 2018 praticados nos EUA&#44; s&#227;o pouco custo&#8208;eficazes<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">14</span></a>&#46; Esta reflex&#227;o&#44; que n&#227;o questiona os resultados dos ensaios cl&#237;nicos&#44; mas faz uma an&#225;lise sobre a sua utilidade nos ganhos em sa&#250;de&#44; vai largamente depender do custo do f&#225;rmaco em cada pa&#237;s e daquilo que &#233; considerado aceit&#225;vel por cada sistema de sa&#250;de a n&#237;vel nacional&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Recomenda&#231;&#245;es do painel para Portugal</span><p id="par0220" class="elsevierStylePara elsevierViewall">Depois de analisada a evid&#234;ncia cl&#237;nica&#44; as an&#225;lises de custo&#8208;efetividade e as recomenda&#231;&#245;es emitidas por outras sociedades cient&#237;ficas&#44; os autores prop&#245;em que se considere a associa&#231;&#227;o de um IPCSK9 nos doentes com terap&#234;utica anti&#8208;dislipid&#233;mica otimizada que tenham tido evento aterotromb&#243;tico pr&#233;vio e tenham&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Valor c&#8208;LDL <span class="elsevierStyleItalic">&#8805;</span> 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dl</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Valor c&#8208;LDL <span class="elsevierStyleItalic">&#8805;</span> 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e um dos seguintes fatores&#58;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8208;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Diabetes com les&#227;o de &#243;rg&#227;o&#8208;alvo &#40;exemplo&#44; protein&#250;ria&#41;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8208;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Doen&#231;a polivascular</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8208;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Doen&#231;a coron&#225;ria significativa multivaso&#44; revascularizada ou n&#227;o</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8208;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Evento cardiovascular recorrente &#40;&#60;5 anos ap&#243;s primeiro evento&#41;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8208;</span><p id="par0255" class="elsevierStylePara elsevierViewall">Hipercolesterolemia familiar</p></li></ul></p><p id="par0260" class="elsevierStylePara elsevierViewall">Antes de se considerar a introdu&#231;&#227;o de IPCSK9 devem verificar&#8208;se &#40;todas&#41; as seguintes condi&#231;&#245;es&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8208;</span><p id="par0265" class="elsevierStylePara elsevierViewall">Tratamento com a dose m&#225;xima tolerada de estatina de alta intensidade &#40;atorvastatina 40&#8208;80<span class="elsevierStyleHsp" style=""></span>mg ou rosuvastatina 20&#8208;40<span class="elsevierStyleHsp" style=""></span>mg&#41;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8208;</span><p id="par0270" class="elsevierStylePara elsevierViewall">Tratamento de associa&#231;&#227;o com ezetimiba 10<span class="elsevierStyleHsp" style=""></span>mg</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8208;</span><p id="par0275" class="elsevierStylePara elsevierViewall">Adequado controlo dos restantes fatores de risco</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8208;</span><p id="par0280" class="elsevierStylePara elsevierViewall">Implementa&#231;&#227;o de altera&#231;&#227;o do estilo de vida&#44; incluindo aconselhamento nutricional e cessa&#231;&#227;o tab&#225;gica &#40;<a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a>&#41;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></li></ul></p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Utiliza&#231;&#227;o dos IPCSK9 na hipercolesterolemia familiar&#44; sem doen&#231;a cardiovascular conhecida</span><p id="par0285" class="elsevierStylePara elsevierViewall">As recomenda&#231;&#245;es da ESC&#47;EAS sobre o uso de IPCSK9 aconselham a sua utiliza&#231;&#227;o em doentes com HeHF sem doen&#231;a cardiovascular estabelecida&#44; de risco CV alto ou muito alto&#44; se tiverem n&#237;veis de c&#8208;LDL &#62; 180<span class="elsevierStyleHsp" style=""></span>mg&#47;dL ap&#243;s a otimiza&#231;&#227;o da terap&#234;utica hipolipemiante<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">77</span></a>&#46; Aconselham ainda que na presen&#231;a de fatores de risco adicionais &#40;diabetes&#44; n&#237;veis elevados de Lp&#40;a&#41;&#44; DCV prematura em familiar de primeiro grau&#44; tabagismo&#44; indicadores de gravidade por imagem&#41; o valor de c&#8208;LDL para se considerar a introdu&#231;&#227;o de IPCSK9 deve ser mais baixo &#40;&#62; 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">Em doentes com HFHo os IPCSK9 s&#227;o recomendados como terap&#234;utica adicional para reduzir os n&#237;veis de c&#8208;LDL&#44; em doentes a fazer ou n&#227;o af&#233;rese das LDL&#46; Por outro lado&#44; em doentes com muta&#231;&#245;es negativa&#47;negativa do r&#8208;LDL&#44; que t&#234;m uma atividade de r&#8208;LDL inferior a 2&#37; n&#227;o se recomenda IPCSK9&#44; porque o seu mecanismo de a&#231;&#227;o implica algum n&#237;vel de atividade do r&#8208;LDL<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">44&#44;54</span></a>&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Recomenda&#231;&#245;es do painel para Portugal</span><p id="par0295" class="elsevierStylePara elsevierViewall">Na hipercolesterolemia familiar&#44; sem evento cardiovascular pr&#233;vio&#44; prop&#245;em&#8208;se que se considere a associa&#231;&#227;o de um iPCSK9 nos doentes que&#44; ap&#243;s terap&#234;utica hipolipemiante otimizada&#44; mantenham&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">1&#46;</span><p id="par0300" class="elsevierStylePara elsevierViewall">Valor c&#8208;LDL &#8805; 180<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#59;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">2&#46;</span><p id="par0305" class="elsevierStylePara elsevierViewall">Valor c&#8208;LDL &#8805; 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e um dos seguintes fatores&#58;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8208;</span><p id="par0310" class="elsevierStylePara elsevierViewall">Diabetes com les&#227;o de &#243;rg&#227;o&#8208;alvo &#40;ex&#46; protein&#250;ria&#41; ou 1 fator de risco <span class="elsevierStyleItalic">major</span></p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8208;</span><p id="par0315" class="elsevierStylePara elsevierViewall">Lipoprote&#237;na &#40;a&#41; &#62; 50<span class="elsevierStyleHsp" style=""></span>mg&#47;dL</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8208;</span><p id="par0320" class="elsevierStylePara elsevierViewall">Fatores de risco <span class="elsevierStyleItalic">major</span>&#58; exemplo&#44; hipertens&#227;o arterial estadio 2 e 3 &#40;PA &#62; 160&#47;100<span class="elsevierStyleHsp" style=""></span>mmHg&#41; n&#227;o controlada</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8208;</span><p id="par0325" class="elsevierStylePara elsevierViewall">Doen&#231;a cardiovascular prematura em familiar 1&#176; grau &#40;homem &#60; 55 anos&#59; mulher &#60; 60 anos&#41;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8208;</span><p id="par0330" class="elsevierStylePara elsevierViewall">Doen&#231;a ateroscler&#243;tica subcl&#237;nica significativa</p></li></ul></p><p id="par0335" class="elsevierStylePara elsevierViewall">Uma vez mais&#44; antes de se considerar a introdu&#231;&#227;o de iPCSK9 devem verificar&#8208;se &#40;todas&#41; as seguintes condi&#231;&#245;es&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8208;</span><p id="par0340" class="elsevierStylePara elsevierViewall">Tratamento com a dose m&#225;xima tolerada de estatina de alta intensidade &#40;atorvastatina 40&#8208;80<span class="elsevierStyleHsp" style=""></span>mg ou rosuvastatina 20&#8208;40<span class="elsevierStyleHsp" style=""></span>mg&#41;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8208;</span><p id="par0345" class="elsevierStylePara elsevierViewall">Tratamento de associa&#231;&#227;o com ezetimiba 10<span class="elsevierStyleHsp" style=""></span>mg</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8208;</span><p id="par0350" class="elsevierStylePara elsevierViewall">Adequado controlo dos restantes fatores de risco cardiovascular</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8208;</span><p id="par0355" class="elsevierStylePara elsevierViewall">Implementa&#231;&#227;o de altera&#231;&#227;o do estilo de vida&#44; incluindo aconselhamento nutricional espec&#237;fico e cessa&#231;&#227;o tab&#225;gica &#40;<a class="elsevierStyleCrossRef" href="#fig0015">figura 3</a>&#41;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></li></ul></p><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Recomenda&#231;&#245;es para a utiliza&#231;&#227;o de iPCSK9 em doentes com intoler&#226;ncia &#224;s estatinas</span><p id="par0360" class="elsevierStylePara elsevierViewall">A maioria dos casos de intoler&#226;ncia &#224; estatina est&#225; diretamente relacionada com queixas subjetivas do doente&#44; sendo as altera&#231;&#245;es laboratoriais &#8211; como causa de descontinua&#231;&#227;o do tratamento &#8208; uma situa&#231;&#227;o menos comum&#46; Assim&#44; na maioria dos casos&#44; a intoler&#226;ncia &#224; estatina n&#227;o deve ser pontuada pela simples ocorr&#234;ncia de sintomas em geral&#44; mas pela presen&#231;a de sintomas percebidos como inaceit&#225;veis&#46; Sendo assim&#44; intoler&#226;ncia &#224; estatina deve ser entendida como uma s&#237;ndrome apurada&#44; atestada e documentada que leva a uma dosagem n&#227;o ideal de estatinas&#44; a menor ader&#234;ncia ao tratamento&#44; a diminui&#231;&#227;o da qualidade de vida do doente&#44; ou &#224; cessa&#231;&#227;o da estatina<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">78&#44;79</span></a>&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">N&#227;o existe uma defini&#231;&#227;o universalmente aceite de intoler&#226;ncia &#224; estatina&#44; mas existem v&#225;rios documentos que procuraram um consenso &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Tabela 1&#44; Suplemento</a>&#41;&#46; Comummente&#44; a intoler&#226;ncia &#224; estatina &#233; tida como a ocorr&#234;ncia de sintomas adversos &#40;quase sempre m&#250;sculo&#8208;esquel&#233;ticos&#41; percebidos como intoler&#225;veis pelo doente e&#47;ou pela presen&#231;a de altera&#231;&#245;es laboratoriais sugestivos de risco indevido &#40;<span class="elsevierStyleItalic">e&#46;g&#46;</span> CK&#44; ALT&#47;AST ou bilirrubina&#41;&#44; atribu&#237;veis ao tratamento com estatinas e que levam &#224; descontinua&#231;&#227;o do tratamento &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Tabela 2&#44; Suplement</a>o&#41;&#46; Na pr&#225;tica&#44; &#233; necess&#225;rio definir melhor a aceitabilidade dos sintomas&#44; a atribui&#231;&#227;o de uma presum&#237;vel causalidade e o grau de real intoler&#226;ncia&#46; Muito frequentemente &#8211; mesmo quando ocorrem durante o tratamento com uma estatina &#8211; os efeitos adversos musculares &#40;ou outros&#41; n&#227;o est&#227;o&#44; de facto&#44; relacionados com o f&#225;rmaco e a larga maioria destes doentes s&#227;o capazes de tolerar o tratamento adequado&#46; Esta identifica&#231;&#227;o dos falsos casos de intoler&#226;ncia &#224;s estatinas &#233; fundamental para evitar a descontinua&#231;&#227;o intempestiva&#44; desnecess&#225;ria e imprudente das estatinas em doentes que delas necessitam<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">80</span></a>&#46; Existem caracter&#237;sticas que ajudam o cl&#237;nico a identificar a maior ou menor probabilidade de causalidade dos sintomas com a toma de estatinas &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Tabela 3&#44; Suplemento</a>&#41;&#44; podendo tamb&#233;m ser utilizado o aplicativo <span class="elsevierStyleItalic">ACC Statin Intolerance</span> ou <span class="elsevierStyleItalic">scores</span> de probabilidade<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">81</span></a>&#46; Al&#233;m disso&#44; deve&#8208;se estar atento a fatores favorecedores de maior risco de intoler&#226;ncia &#224;s estatinas ou capazes de desencadear as manifesta&#231;&#245;es sintom&#225;ticas&#44; que devem ser tamb&#233;m avaliados &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Tabela 4&#44; Suplemento</a>&#41;&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall">Face &#224; grande varia&#231;&#227;o dos doentes em rela&#231;&#227;o ao n&#250;mero e &#224; dosagem de estatinas que s&#227;o incapazes de tolerar&#44; do ponto de vista pr&#225;tico&#44; podem&#8208;se ponderar dois graus de intoler&#226;ncia &#224;s estatinas&#58; &#40;1&#41; <span class="elsevierStyleItalic">a intoler&#226;ncia completa &#224; estatina</span> assente na incapacidade de tolerar um m&#237;nimo de tr&#234;s estatinas &#40;ainda que na menor dose di&#225;ria&#58; atorvastatina 10<span class="elsevierStyleHsp" style=""></span>mg&#44; fluvastatina 40<span class="elsevierStyleHsp" style=""></span>mg&#44; lovastatina 20<span class="elsevierStyleHsp" style=""></span>mg&#44; pitavastatina 2<span class="elsevierStyleHsp" style=""></span>mg&#44; pravastatina 40<span class="elsevierStyleHsp" style=""></span>mg&#44; rosuvastatina 5<span class="elsevierStyleHsp" style=""></span>mg e sinvastatina 20<span class="elsevierStyleHsp" style=""></span>mg&#41;&#59; e &#40;2&#41; <span class="elsevierStyleItalic">a intoler&#226;ncia parcial &#224;s estatinas</span> definida pela impossibilidade de tolerar a estatina na posologia necess&#225;ria ao atingimento do objetivo terap&#234;utico pretendido&#46; Esta &#250;ltima deve ser entendida&#44; de forma pragm&#225;tica&#44; de acordo com as necessidades terap&#234;uticas e os objetivos apontados em cada doente&#44; de modo que a intoler&#226;ncia a algumas estatinas &#40;ou a determinada posologia&#41; n&#227;o deve ser imprudentemente tida como intoler&#226;ncia &#224; estatina&#44; desde que n&#227;o interfira com o atingimento dos objetivos terap&#234;uticos&#46;</p><p id="par0375" class="elsevierStylePara elsevierViewall">Apesar da utiliza&#231;&#227;o de IPCSK9 em doentes intoler&#226;ncia &#224;s estatinas ser l&#243;gica e consensual&#44; esta n&#227;o &#233; indica&#231;&#227;o formalmente aprovada nas atuais indica&#231;&#245;es para a utiliza&#231;&#227;o dos iPCSK9<span class="elsevierStyleHsp" style=""></span>da EMEA&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Recomenda&#231;&#245;es do painel</span><p id="par0380" class="elsevierStylePara elsevierViewall">Em resumo&#44; a administra&#231;&#227;o de iPCSK9 deve ser considerada nos doentes incapazes de tolerar o tratamento com doses apropriadas de&#44; pelo menos&#44; tr&#234;s estatinas&#44; especialmente se coexistirem outros &#237;ndices de gravidade acrescida &#40;<span class="elsevierStyleItalic">e&#46;g&#46;</span> hipercolesterolemia familiar&#44; doen&#231;a polivascular ou multivasos ou doen&#231;a cardiovascular de natureza ateroscler&#243;tica rapidamente progressiva&#41;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">77</span></a>&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Gest&#227;o cl&#237;nica do doente sob terap&#234;utica com iPCSK9</span><p id="par0385" class="elsevierStylePara elsevierViewall">Os iPCSK9 devem ser prescritos em consulta hospitalar dedicada &#224; gest&#227;o de risco CV sob a coordena&#231;&#227;o de especialidades m&#233;dicas hospitalares&#46; Esta consulta deve ser baseada em protocolos de diagn&#243;stico e tratamento pr&#233;&#8208;estabelecidos&#44; elaborados por uma equipa multidisciplinar&#46;</p><p id="par0390" class="elsevierStylePara elsevierViewall">A elegibilidade para a eventual terap&#234;utica com iPCSK9 deve ser avaliada ap&#243;s otimiza&#231;&#227;o da terap&#234;utica farmacol&#243;gica com estatina na dose m&#225;xima tolerada e ezetimiba&#44; mas tamb&#233;m ap&#243;s otimiza&#231;&#227;o da terap&#234;utica n&#227;o farmacol&#243;gica&#44; com particular &#234;nfase na dieta orientada por nutricionista e controlo de outros fatores de risco CV&#44; incluindo o tabagismo <a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">6&#44;77</span></a>&#46; A avalia&#231;&#227;o para terap&#234;utica com iPCSK9 deve incluir a confirma&#231;&#227;o de ades&#227;o ao tratamento com estatina na dose m&#225;xima tolerada e ezetimiba&#44; podendo ser necess&#225;rio reavaliar o perfil lip&#237;dico ap&#243;s um per&#237;odo de quatro semanas com ades&#227;o plena&#44; se apropriado&#46; Recomenda&#8208;se ainda a avalia&#231;&#227;o da fun&#231;&#227;o renal e hep&#225;tica antes do in&#237;cio do tratamento&#46;</p><p id="par0395" class="elsevierStylePara elsevierViewall">O in&#237;cio do tratamento com um iPCSK9 constitui uma oportunidade para a implementa&#231;&#227;o de um programa de ensino multidisciplinar e estruturado ao doente&#44; visando a doen&#231;a ateroscler&#243;tica e a terap&#234;utica espec&#237;fica&#44; com eventual recurso a material multim&#233;dia e did&#225;tico&#46;</p><p id="par0400" class="elsevierStylePara elsevierViewall">A administra&#231;&#227;o inicial do anticorpo monoclonal anti&#8208;PCSK9 deve ser efetuada em ambiente hospitalar&#44; seguida de vigil&#226;ncia durante um per&#237;odo de 30 minutos&#46; As administra&#231;&#245;es seguintes poder&#227;o ser efetuadas no domic&#237;lio&#44; ap&#243;s o ensino do doente ou do seu cuidador&#46;</p><p id="par0405" class="elsevierStylePara elsevierViewall">O efeito hipolipemiante da terap&#234;utica deve ser avaliado cerca de quatro semanas ap&#243;s o in&#237;cio do tratamento&#46; No caso de o doente ser hiporrespondedor &#40;redu&#231;&#227;o do c&#8208;LDL&#60;25&#37;&#41; deve ser considerada a descontinua&#231;&#227;o da terap&#234;utica&#46; Nos indiv&#237;duos que atinjam valores de c&#8208;LDL&#60;25<span class="elsevierStyleHsp" style=""></span>mg&#47;dl deve ser considerada a redu&#231;&#227;o da dose<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">13</span></a>&#46;</p><p id="par0410" class="elsevierStylePara elsevierViewall">A monitoriza&#231;&#227;o do efeito hipolipemiante deve ser mantida com uma periodicidade pelo menos semestral e os efeitos adversos devem ser reportados ao Sistema Nacional de Farmacovigil&#226;ncia &#40;<a class="elsevierStyleCrossRef" href="#fig0020">figura 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclus&#227;o</span><p id="par0415" class="elsevierStylePara elsevierViewall">Os iPCSK9 s&#227;o uma nova op&#231;&#227;o terap&#234;utica que permite uma redu&#231;&#227;o significativa dos valores de c&#8208;LDL e do risco de eventos CV&#44; em doentes j&#225; medicados com terap&#234;utica hipolipemiante otimizada&#46;</p><p id="par0420" class="elsevierStylePara elsevierViewall">Estas recomenda&#231;&#245;es para a utiliza&#231;&#227;o dos iPCSK9 na pr&#225;tica cl&#237;nica em Portugal&#44; s&#227;o o resultado de uma reflex&#227;o multidisciplinar&#44; tentando integrar uma estrat&#233;gia de privilegiar a sua administra&#231;&#227;o aos doentes que mais possam beneficiar&#44; ou seja&#44; aqueles que t&#234;m simultaneamente maior risco e valores absolutos de c&#8208;LDL mais elevados&#46; Como com todas as recomenda&#231;&#245;es&#44; a sua aplica&#231;&#227;o na pr&#225;tica cl&#237;nica n&#227;o substitui a avalia&#231;&#227;o cl&#237;nica individual de cada doente&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflits of interst</span><p id="par0425" class="elsevierStylePara elsevierViewall">RFC received advisory or speaker fees from MSD&#44; Bial and Amgen&#46;</p><p id="par0430" class="elsevierStylePara elsevierViewall">PMS has received advisory or speaker fees from Bayer&#44; JABA&#8208;Recordati&#44; MSD Portugal&#44; Kowa Pharmaceuticals&#44; Novartis&#44; Daiichi Sankyo&#44; Amgen&#44; Sanofi&#8208;Regeneron e Tecnimede&#46;</p><p id="par0435" class="elsevierStylePara elsevierViewall">FA reports no conflts of interest&#46;</p><p id="par0440" class="elsevierStylePara elsevierViewall">CG received advisory or speaker fees from MSD&#44; Amgen&#46;</p><p id="par0445" class="elsevierStylePara elsevierViewall">JF has received advisory fees from Amgen&#46;</p><p id="par0450" class="elsevierStylePara elsevierViewall">JM has received advisory or speaker fees from Astra Zeneca&#44; Amgen&#44; Bayer&#44; Boehringer Ingelheim&#44; Jaba&#44; Servier&#44; Novartis&#46;</p></span></span>"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">RNA&#58; &#193;cido ribonucleico</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tecnologia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Agente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Programa de Investiga&#231;&#227;o Cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Fase de Investiga&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpo monoclonal anti&#8208;PCSK9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alirocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aprova&#231;&#227;o pela EMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bococizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SPIRE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Descontinuado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evolocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PROFICIO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aprova&#231;&#227;o pela EMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Inativa&#231;&#227;o do gene do PCSK9</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pequeno RNA de interfer&#234;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inclisiran&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ORION&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fase III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Oligonucle&#243;tido antisentido&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMS&#8208;84442&#44; SPC5001&#44; SPC4061&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fase I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Descontinuados&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Pequenas mol&#233;culas inibidoras da PCSK9</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Adnectina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMS&#8208;962476&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fase I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anexina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anexina A2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pr&#233;&#8208;cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Vacina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AT04A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pr&#233;&#8208;Cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Colesterol total&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">C&#8208;LDL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">C&#8208;HDL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Lp&#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ApoB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alirocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;39&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;60&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-6&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;9&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;26&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;50&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bococizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;34&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;57&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-6&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;14&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;24&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;46&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evolocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;42&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;71&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-12&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;17&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;45&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;56&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Diferen&#231;a na varia&#231;&#227;o percentual dos par&#226;metros lip&#237;dicos&#44; entre os AM anti&#8208;PCSK9 e placebo &#224;s 12&#47;24 semanas&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">34&#44;35</span></a></p>"
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Os valores dos par&#226;metros lip&#237;dicos s&#227;o expressos em mg&#47;dl&#46; ApoB&#58; Apolipoprote&#237;na B&#59; AVC&#58; Acidente vascular cerebral&#59; C&#8208;LDL&#58; Colesterol das lipoprote&#237;nas de baixa densidade &#40;mg&#47;dl&#41;&#59; C&#8208;n&#227;oHDL&#58; Colesterol das lipoprote&#237;nas n&#227;o alta densidade &#40;mg&#47;dl&#41; CV&#58; Cardiovascular&#59; DAP&#58; Doen&#231;a arterial perif&#233;rica&#59; EM&#58; Enfarte do mioc&#225;rdio&#59; SCA&#58; s&#237;ndroma coron&#225;ria aguda&#59; Sem&#58; Semanas&#59; 1<span class="elsevierStyleHsp" style=""></span>&#170;&#58; Prim&#225;ria&#59; 2<span class="elsevierStyleHsp" style=""></span>&#170;&#58; Secund&#225;ria&#59;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ODISSEY Outcomes<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SPIRE&#8208;1<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SPIRE&#8208;2<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FOURIER<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Agente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alirocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bococizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evolocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">75 ou 150<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem &#40;ajustado para atingir c&#8208;LDL alvo 25&#8208;50mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">150<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem&#40;reduzido para 75<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem se c&#8208;LDL&#60;10&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">140<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem ou420<span class="elsevierStyleHsp" style=""></span>mg 4&#47;4 sem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#250;mero de doentes inclu&#237;dos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18924&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16817&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10621&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27564&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Popula&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SCA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Preven&#231;&#227;o 2<span class="elsevierStyleHsp" style=""></span>&#170; &#40;84&#37;&#41; ou1<span class="elsevierStyleHsp" style=""></span>&#170; com risco CV elevado &#40;16&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EAM &#40;81&#37;&#41;&#44; AVC &#40;19&#37;&#41; ou DAP &#40;13&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Idade m&#233;dia &#40;anos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetes &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elegibilidade &#8211; L&#237;pidos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#62;&#61;70 ou c&#8208;n&#227;oHDL &#62;&#61;100 ou ApoB &#62;&#61;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#62;&#61;70 ou c&#8208;n&#227;oHDL &#62;&#61;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#62;&#61;100 ou c&#8208;n&#227;oHDL&#62;&#61;130&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#62;&#61;70 ou c&#8208;n&#227;oHDL &#62;&#61;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL basal &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL atingido no estudo &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#40;<span class="elsevierStyleItalic">vs&#46;</span> 101 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#40;<span class="elsevierStyleItalic">vs&#46;</span> 100 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#40;<span class="elsevierStyleItalic">vs&#46;</span> 137 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#40;<span class="elsevierStyleItalic">vs&#46;</span> 86 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Estatina em dose intensiva &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dura&#231;&#227;o do estudo &#40;anos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resultado Prim&#225;rio &#40;HR e IC 95&#37;&#41; &#47; NNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85&#40;0&#44;78&#8208;0&#44;93&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>NNT&#58; 63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;99 &#40;0&#44;80&#8208;1&#44;22&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;79 &#40;0&#44;65&#8208;0&#44;97&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85&#40;0&#44;79&#8208;0&#44;92&#41;&#176;NNT&#58; 67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte CV&#44; EM ou AVC &#40;HR e IC 95&#37;&#41; &#47; NNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86&#40;0&#44;79&#8208;0&#44;93&#41;&#176;&#176;NNT&#58; 63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;03 &#40;0&#44;82&#8208;1&#44;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;60&#8208;0&#44;92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;80 &#40;0&#44;73&#8208;0&#44;88&#41; NNT&#58; 67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte CV &#40;HR e IC 95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;88&#40;0&#44;74&#8208;1&#44;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;20 &#40;0&#44;74&#8208;1&#44;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;82 &#40;0&#44;50&#8208;1&#44;36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;05 &#40;0&#44;88&#8208;1&#44;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EM &#40;HR e IC 95&#37;&#41; &#47; NNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;77&#8208;0&#44;96&#41;<span class="elsevierStyleSup">X</span> NNT&#58; 100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;11 &#40;0&#44;83&#8208;1&#44;48&#41;<span class="elsevierStyleSup">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;76 &#40;0&#44;58&#8208;1&#44;00&#41;<span class="elsevierStyleSup">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;73 &#40;0&#44;65&#8208;0&#44;82&#41; NNT&#58; 84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AVC &#40;HR e IC 95&#37;&#41; &#47; NNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;73 &#40;0&#44;57&#8208;0&#44;93&#41; NNT&#58; 250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;52 &#40;0&#44;30&#8208;0&#44;91&#41;<span class="elsevierStyleSup">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;66 &#40;0&#44;40&#8208;1&#44;09&#41;<span class="elsevierStyleSup">X</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;79 &#40;0&#44;66&#8208;0&#44;95&#41; NNT&#58; 250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Ensaio cl&#237;nico&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Redu&#231;&#227;o Lp&#40;a&#41; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Estudos com Evolocumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RUTHERFORD &#8208;2<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">52</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHe&#40;12 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">140<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem&#58; &#8208;59&#44;2&#37; 420<span class="elsevierStyleHsp" style=""></span>mg 4&#47;4 sem&#58; &#8208; 61&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">140<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem&#58; &#8208; 31&#44;6&#37; 420<span class="elsevierStyleHsp" style=""></span>mg 4&#47;4 sem&#58; &#8208; 28&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TESLA parte A<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">53</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHo&#40;36 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#47;4 sem&#58; &#8208; 16&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#47;4 sem&#58; &#8208; 11&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;2 sem&#58; &#8208; 13&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;2 sem&#58; &#8208; 18&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TESLA parte B<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">44</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHo&#40;12 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 30&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 11&#44;8&#37; &#40;p&#61;0&#44;09&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TAUSSIG<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">54</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HF grave&#40;5 anos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em curso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Estudos com Alirocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY FH I e FH II<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">55</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHe&#40;78 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FH I&#58; &#8208; 57&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FH I&#58; &#8208; 17&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FH II&#58; &#8208; 51&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FH II&#58; &#8208; 20&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY HIGH<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">56</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHe&#40;78 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 39&#44;1&#37; &#224; sem 24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 14&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY LONG TERM<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">57</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHe&#40;78 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 61&#44;9&#37; &#224; sem 24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 25&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY OLE<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHe&#40;176 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em curso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t" scope="col">Evento&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FOURIER<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">11</span></a></th></tr><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Bococizumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Evolocumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Evento adverso&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">75&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">77&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">63&#44;7&#37;<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">60&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">77&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">77&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Evento adverso grave&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">19&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">24&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">24&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Rea&#231;&#227;o local inje&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#44;8&#37;<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">10&#44;4&#37;<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#44;1&#37;<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Diabetes <span class="elsevierStyleItalic">mellitus</span> de novo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">10&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">7&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evento neurocognitivo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Eleva&#231;&#227;o ALT&#40;&#62;3x&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Eleva&#231;&#227;o CK<a class="elsevierStyleCrossRef" href="#tblfn0020">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpo neutralizante do inibidor PCSK9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Perfil de doente em preven&#231;&#227;o secund&#225;ria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Limiar de c&#8208;LDL para ser considerada introdu&#231;&#227;o IPCSK9<a class="elsevierStyleCrossRef" href="#tblfn0025">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recomenda&#231;&#245;es NICE<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">73</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evento cardiovascular pr&#233;vio&#40;SCA&#44; AVC isqu&#233;mico&#44; revasculariza&#231;&#227;o coron&#225;ria ou arterial&#44; doen&#231;a coron&#225;ria ou doen&#231;a arterial perif&#233;rica&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 150 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a polivascularouEventos CV recorrentes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805;130 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recomenda&#231;&#245;es Sociedade Espanhola Cardiologia<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">74</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SCA &#60; 12 meses &#43; Dislipidemia familiar&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 70 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a coron&#225;ria est&#225;vel ou SCA pr&#233;vio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 100 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SCA recorrente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 70 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a coron&#225;ria &#43; intoler&#226;ncia&#47;contra&#8208;indica&#231;&#227;o estatinas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Conforme o valor alvo de c&#8208;LDL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recomenda&#231;&#245;es ESC&#47;ESA<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">75</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a cardiovascular cl&#237;nica&#40;SCA&#44; doen&#231;a arterial perif&#233;rica&#44; AVC pr&#233;vios&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805;140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a cardiovascular cl&#237;nica &#43; 1 dos seguintes&#58;&#8208;Dislipidemia Familiar&#8208;Diabetes com LOA ou um fator risco <span class="elsevierStyleItalic">major</span>&#8208;Doen&#231;a cardiovascular grave ou extensa &#40;p&#46;e&#46; polivascular&#41;&#8208;R&#225;pida progress&#227;o DCV &#40;recorr&#234;ncia de SCA&#44; revasculariza&#231;&#227;o coron&#225;ria repetida ou AVC isqu&#233;mico recorrente&#44; nos primeiros 5 anos ap&#243;s um primeiro evento&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recomenda&#231;&#245;es ACC&#47;AHA<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">76</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a ateroscler&#243;tica estabelecida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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Perspetivas em Cardiologia
Guia prático para a utilização dos inibidores da PCSK9 em Portugal
Practical guide for the use of PCSK9 inhibitors in Portugal
Ricardo Fontes‐Carvalhoa,b,
Autor para correspondência
fontes.carvalho@gmail.com

Autor para correspondência.
, Pedro Marques Silvac, Elisabete Rodriguesd,e, Francisco Araújof, Cristina Gavinae,g, Jorge Ferreirah, João Moraisi
a Departamento de Cardiologia, Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal
b Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
c Núcleo de Investigação Arterial, Hospital de Santa Marta, Centro Hospitalar de Lisboa Central, Lisboa, Portugal
d Departamento de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar S. João, Porto, Portugal
e Departamento de Medicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
f Serviço de Medicina Interna, Hospital Beatriz Ângelo, Loures, Portugal
g Serviço de Cardiologia, Hospital Pedro Hispano ‐ Unidade Local de Saúde de Matosinhos, Senhora da Hora, Portugal
h Serviço de Cardiologia, Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal
i Serviço de Cardiologia, Centro Hospitalar de Leiria, Leiria, Portugal
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plasm&#225;tico e o risco de doen&#231;a ateroscler&#243;tica&#44; confirmando que o c&#8208;LDL como fator causal direto no desenvolvimento desta doen&#231;a<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Por outro lado&#44; existe evid&#234;ncia inequ&#237;voca de que a redu&#231;&#227;o dos valores de c&#8208;LDL permite a redu&#231;&#227;o proporcional do risco de eventos cardiovasculares<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">3&#44;4</span></a>&#46; Por isso&#44; as <span class="elsevierStyleItalic">guidelines</span> recomendam&#44; de forma consistente&#44; que a terap&#234;utica antidislipid&#233;mica seja ajustada de acordo com &#171;valores&#8208;alvo&#187; de c&#8208;LDL&#44; que devem ser individualizados de acordo com o risco cardiovascular do doente<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">5&#8211;7</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Contudo&#44; os v&#225;rios estudos mostram que existe uma elevada percentagem de doentes que n&#227;o atingem o controlo efetivo dos fatores de risco cardiovascular &#40;CV&#41;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">8</span></a>&#46; Em Portugal&#44; o estudo DYSIS &#40;<span class="elsevierStyleItalic">Dyslipidemia International Study</span>&#8208;Portugal&#41; mostrou que 63&#37; dos portugueses n&#227;o atingem os valores recomendados de c&#8208;LDL<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">9</span></a>&#46; Existem m&#250;ltiplos fatores respons&#225;veis por este mau controlo dos valores de c&#8208;LDL que s&#227;o dependentes do doente &#40;como a m&#225; ader&#234;ncia e a n&#227;o persist&#234;ncia com a terap&#234;utica&#41;&#44; do m&#233;dico &#40;em especial a in&#233;rcia cl&#237;nica&#41;&#44; e da terap&#234;utica &#40;designadamente a variabilidade interindividual e a efic&#225;cia limitada da terap&#234;utica hipolipemiante&#41;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">5&#44;10</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Nos &#250;ltimos anos&#44; os f&#225;rmacos inibidores da PCSK9 &#40;iPCSK9&#41; surgiram como uma nova op&#231;&#227;o terap&#234;utica que permite uma redu&#231;&#227;o significativa e consistente dos valores de c&#8208;LDL &#40;&#8764;50&#8208;60&#37;&#41; que&#44; por sua vez&#44; se traduziu em v&#225;rios ensaios cl&#237;nicos numa redu&#231;&#227;o adicional do risco de eventos cardiovasculares<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">11&#8211;13</span></a>&#46; Contudo&#44; a terap&#234;utica com iPCSK9 tem custos elevados&#44; pelo que a sua utiliza&#231;&#227;o cl&#237;nica deve ser criteriosa&#44; tendo em considera&#231;&#227;o os dados de custo&#8208;efetividade destes f&#225;rmacos e a manuten&#231;&#227;o da sustentabilidade do sistema de sa&#250;de<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">14</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Este documento baseado no consenso entre autores de v&#225;rias especialidades m&#233;dicas &#40;Cardiologia&#44; 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e passa pelo aparelho de Golgi antes de ser secretada &#40;passo 3&#41;&#46; Na superf&#237;cie do hepat&#243;cito o recetor do LDL &#40;LDL&#8208;R&#41; liga&#8208;se ao c&#8208;LDL circulante e este complexo &#233; internalizado para os endossomas no interior do hepat&#243;cito &#40;passo 4&#41;&#46; Em seguida o LDL&#8208;R recircula para a superf&#237;cie do hepat&#243;cito &#40;passo 5&#41;&#44; processo que ocorre cerca de 150 vezes e que permite que mais c&#8208;LDL seja removido da circula&#231;&#227;o&#46; A PCSK9 regula a quantidade de recetores de LDL na superf&#237;cie do hepat&#243;cito&#44; uma vez que quando se liga a este recetor causa a sua internaliza&#231;&#227;o e destrui&#231;&#227;o no lisossoma &#40;passos 6 e 7&#41;&#44; impedindo o LDL&#8208;R de recircular para a superf&#237;cie do hepat&#243;cito&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Os inibidores da PCSK9 s&#227;o anticorpos monoclonais que se ligam &#224; PCSK9 impedindo&#8208;a de se ligar ao recetor do LDL&#44; aumentando assim a quantidade de recetores de LDL na superf&#237;cie do hepat&#243;cito o que permite uma redu&#231;&#227;o significativa dos valores circulantes de c&#8208;LDL<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">25</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">O gene que codifica a PCSK9 foi identificado h&#225; cerca de 15 anos em conex&#227;o com o fen&#243;tipo de hipercolesterolemia familiar&#44; que rapidamente se demonstrou estar associado a uma muta&#231;&#227;o com ganho de fun&#231;&#227;o<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">26&#44;27</span></a>&#46; A identifica&#231;&#227;o subsequente de variantes do PCSK9 com perda de fun&#231;&#227;o&#44; associadas a n&#237;veis de c&#8208;LDL s&#233;rico baixos e menor risco de DCV criou o modelo farmacol&#243;gico para o aparecimento dos inibidores da PCSK9<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">28</span></a>&#46; Rapidamente se desenvolveram anticorpos monoclonais &#40;mAb&#41; contra a PCSK9&#44; dando origem a programas abrangentes de investiga&#231;&#227;o cl&#237;nica para testar a efic&#225;cia cl&#237;nica dos iPCSK9 na redu&#231;&#227;o de eventos cardiovasculares<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">29</span></a>&#46; Em paralelo&#44; continuam a ser desenvolvidas outras formas alternativas de inibi&#231;&#227;o do PCSK9 conforme detalhado na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a><a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">30&#44;31</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Anticorpos monoclonais anti&#8208;PCSK9 &#40;IPCSK9&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Os anticorpos monoclonais ligam&#8208;se &#224; PCSK9 impedindo a sua fixa&#231;&#227;o ao r&#8208;LDL e a consequente degrada&#231;&#227;o no lisossoma&#44; aumentando o n&#250;mero de recetores de LDL &#40;<a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">25</span></a>&#46; Foram desenvolvidos tr&#234;s anticorpos&#58; o alirocumab&#44; o bococizumab e o evolocumab&#46; O alirocumab e o evolocumab s&#227;o imunoglobulinas totalmente humanas&#44; dos isotipos G1 e G2&#44; respetivamente&#46; Por outro lado&#44; o bococizumab &#233; um anticorpo monoclonal humanizado do isotipo G2&#46; Todos s&#227;o administrados por via subcut&#226;nea e&#44; como s&#227;o anticorpos completos&#44; apresentam uma semivida longa&#44; compat&#237;vel com uma administra&#231;&#227;o em cada 2 a 4 semanas&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Efeito no perfil lip&#237;dico</span><p id="par0070" class="elsevierStylePara elsevierViewall">Ap&#243;s a administra&#231;&#227;o subcut&#226;nea &#40;SC&#41; de 140&#8208;420<span class="elsevierStyleHsp" style=""></span>mg de evolocumab&#44; o pico mediano das concentra&#231;&#245;es s&#233;ricas &#233; alcan&#231;ado em tr&#234;s&#8208;quatro dias&#46; A biodisponibilidade absoluta &#233; de 72&#37; e a semivida &#40;t&#189;&#41; efetiva de 11&#8208;17 dias&#46; A administra&#231;&#227;o SC continuada determina um aumento de exposi&#231;&#227;o ao f&#225;rmaco proporcional &#224; dose&#44; alcan&#231;ando um estado de equil&#237;brio das concentra&#231;&#245;es s&#233;ricas m&#237;nimas &#224;s 12 semanas&#46; A administra&#231;&#227;o &#250;nica SC de evolocumab determina a supress&#227;o m&#225;xima precoce&#44; quase completa&#44; &#224;s quatro horas da PCSK9 livre circulante&#44; com um nadir m&#233;dio na redu&#231;&#227;o do LDL&#8208;C em 14&#8208;21 dias&#46; As varia&#231;&#245;es da PCSK9 livre e das lipoprote&#237;nas s&#233;ricas s&#227;o revers&#237;veis&#44; ap&#243;s a descontinua&#231;&#227;o do tratamento&#44; sem qualquer evid&#234;ncia de efeito de retoma &#40;<span class="elsevierStyleItalic">rebound</span>&#41;&#46; As caracter&#237;sticas farmacocin&#233;ticas do alirocumab s&#227;o compar&#225;veis&#46; Ap&#243;s a administra&#231;&#227;o SC&#44; os tempos m&#233;dios para a concentra&#231;&#227;o s&#233;rica m&#225;xima &#40;tmax&#41; s&#227;o tr&#234;s&#8208;sete dias&#44; a sua biodisponibilidade absoluta &#233; &#8776; 85&#37; e o estado estacion&#225;rio &#233; obtido ap&#243;s 2&#8208;3 doses&#46; A semivida m&#233;dia aparente &#233; de 17&#8208;20 dias<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">32&#44;33</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Os anticorpos monoclonais anti&#8208;PCSK9 reduzem os n&#237;veis de C&#8208;LDL em cerca de 60&#37;&#44; conforme demonstrado em v&#225;rios estudos de curta dura&#231;&#227;o &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">34&#44;35</span></a>&#44; independentemente da terap&#234;utica antidislipid&#233;mica de base<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">36</span></a>&#46; Contudo&#44; a efic&#225;cia &#233; ligeiramente maior nos doentes medicados com estatina devido ao aumento da express&#227;o do gene do PCSK9<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">37</span></a>&#46; Al&#233;m da redu&#231;&#227;o do c&#8208;LDL&#44; esta classe permite uma redu&#231;&#227;o do colesterol total de cerca de 38&#37;&#44; da apolipoprote&#237;na B &#40;ApoB&#41; de 50&#37; e a da lipoprote&#237;na &#40;a&#41; &#91;Lp&#40;a&#41;&#93; de 28&#37;&#46; Tamb&#233;m em doentes intolerantes &#224;s estatinas a sua utiliza&#231;&#227;o permitiu uma redu&#231;&#227;o do c&#8208;LDL de 51&#44;4&#37;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">38&#8211;41</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">A longo prazo&#44; a efic&#225;cia na redu&#231;&#227;o do c&#8208;LDL manteve&#8208;se para o alirocumab &#40;&#8208;54&#44;7&#37; aos 48 meses&#41; e para o evolocumab &#40;&#8208;54&#44;0&#37; aos 39 meses&#41; nos ensaios de eventos CV<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">11&#44;13</span></a>&#46; Contudo&#44; em rela&#231;&#227;o ao bococizumab &#8208; que &#233; um anticorpo humanizado da PCSK9 &#8208; observou&#8208;se uma atenua&#231;&#227;o da sua efic&#225;cia &#40;&#8208;38&#44;3&#37; aos 24 meses&#41;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a>&#44; geralmente atribu&#237;da ao desenvolvimento de anticorpos neutralizantes do bococizumab&#44; efeito que ocorre em cerca de 30&#37; dos doentes ao fim de um ano&#44; o que levou &#224; interrup&#231;&#227;o do seu programa de desenvolvimento cl&#237;nico<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">35</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">De acordo com a sua farmacodin&#226;mica&#44; os anticorpos monoclonais anti&#8208;PCSK9 s&#227;o eficazes na redu&#231;&#227;o do c&#8208;LDL em todos os doentes que sejam capazes de expor r&#8208;LDL hep&#225;ticos&#46; Nos v&#225;rios estudos realizados em doentes com hipercolesterolemia familiar heterozig&#243;tica &#40;HeHF&#41; sob estatina&#44; com ou sem ezetimiba&#44; os anticorpos monoclonais anti&#8208;PCSK9 reduziram significativamente os valores de c&#8208;LDL &#40;entre 39&#44;1&#37; e 61&#44;3&#37;&#41;&#44; independentemente do tipo de muta&#231;&#227;o do r&#8208;LDL<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">42</span></a>&#46; Na HF homozig&#243;tica &#40;HoHF&#41;&#44; a efic&#225;cia do evolocumab na redu&#231;&#227;o do c&#8208;LDL foi muito vari&#225;vel&#44; observando&#8208;se varia&#231;&#245;es percentuais de 22&#44;9&#37; a 40&#44;8&#37; nos doentes com pelo menos um alelo com muta&#231;&#227;o defeituosa no gene r&#8208;LDL<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">42&#8211;44</span></a>&#46; Os doentes com HoHF&#44; com d&#233;fice duplo do r&#8208;LDL&#44; naturalmente&#44; respondem de forma muito deficiente ao tratamento&#46; T&#234;m sido descritos casos raros de aus&#234;ncia de resposta ou de resposta atenuada aos iPCSK9&#46; A variabilidade de resposta est&#225; presente na hipercolesterolemia autoss&#243;mica recessiva &#40;por muta&#231;&#227;o da prote&#237;na adaptadora do recetor de LDL tipo 1 &#8208; LDLRAP1 &#8211; que participa na internaliza&#231;&#227;o do complexo r&#8208;LDLR&#47;c&#8208;LDL no hepat&#243;cito e&#44; consequentemente determina um aumento do c&#8208;LDL&#41; ou na muta&#231;&#227;o R410S do r&#8208;LDL que leva tamb&#233;m a uma altera&#231;&#227;o no metabolismo do r&#8208;LDL nos endossomas&#46; A avalia&#231;&#227;o gen&#233;tica poder&#225; estar assim indicada nos doentes n&#227;o respondedores aos iPCSK9&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">De notar ainda que esta classe terap&#234;utica n&#227;o reduziu os valores de prote&#237;na C&#8208;reativa&#44; o que pode sugerir que o impacto das estatinas neste biomarcador seja um efeito pleiotr&#243;pico independente da redu&#231;&#227;o do c&#8208;LDL<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">45&#44;46</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Estudos de eventos cardiovasculares</span><p id="par0095" class="elsevierStylePara elsevierViewall">Os anticorpos monoclonais anti&#8208;PCSK9 foram avaliados em quatro ensaios cl&#237;nicos de eventos CV aleatorizados e controlados com placebo&#44; que inclu&#237;ram mais de 70 mil doentes&#44; maioritariamente em preven&#231;&#227;o secund&#225;ria conforme detalhado na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a><a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">11&#8211;13</span></a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">O ensaio cl&#237;nico FOURIER&#44; que testou a utiliza&#231;&#227;o do evolucumab&#44; numa popula&#231;&#227;o de doentes est&#225;veis&#44; mas com doen&#231;a vascular estabelecida&#44; foi o primeiro a demonstrar a redu&#231;&#227;o de eventos CV com os IPCSK9 numa popula&#231;&#227;o de 27 564 doentes em preven&#231;&#227;o secund&#225;ria &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">11</span></a>&#46; Neste estudo o evolocumab reduziu significativamente o risco relativo do resultado prim&#225;rio combinado de morte CV&#44; enfarte do mioc&#225;rdio &#40;EM&#41;&#44; acidente vascular cerebral &#40;AVC&#41;&#44; internamento por angina inst&#225;vel &#40;AI&#41; ou revasculariza&#231;&#227;o coron&#225;ria &#40;RC&#41; em 15&#37;&#46; Observaram&#8208;se redu&#231;&#245;es significativas no risco relativo de EM &#40;27&#37;&#41;&#44; AVC &#40;21&#37;&#41; e RC &#40;22&#37;&#41;&#46; O evolocumab n&#227;o reduziu o risco de morte CV e de AI&#46; Os resultados foram consistentes independentemente do c&#8208;LDL basal e da terap&#234;utica anti&#8208;dislipid&#233;mica de base&#46; O efeito do evolocumab nos eventos CV foi mais acentuado depois do primeiro ano de tratamento&#44; traduzido numa redu&#231;&#227;o de 19&#37; no risco relativo do resultado prim&#225;rio e de 25&#37; no resultado secund&#225;rio principal em compara&#231;&#227;o com o placebo&#44; tal como foi observado nos ensaios cl&#237;nicos com estatinas<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">18</span></a>&#46; A magnitude da redu&#231;&#227;o do risco relativo de eventos CV com o evolocumab por unidade de redu&#231;&#227;o do c&#8208;LDL &#40;mmol&#47;l&#41; foi sobrepon&#237;vel &#224; descrita na an&#225;lise do <span class="elsevierStyleItalic">Cholesterol Treatment Trialists Collaboration</span> &#40;CTTC&#41;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">3</span></a>&#46; Na an&#225;lise por redu&#231;&#227;o do risco absoluto do resultado prim&#225;rio e do secund&#225;rio principal o benef&#237;cio foi mais acentuado nos doentes de risco mais elevado&#46; Efetivamente&#44; observaram&#8208;se valores do n&#250;mero necess&#225;rio tratar &#40;NNT&#41; mais baixos nos indiv&#237;duos com doen&#231;a multivaso&#44; EM recorrente ou EM h&#225; menos de dois anos &#40;NNT 34 e 40&#44; respetivamente&#41;&#44; com doen&#231;a arterial perif&#233;rica &#40;NNT 29 para os dois resultados cl&#237;nicos&#41; ou com &#237;ndice de risco TIMI 2<span class="elsevierStyleSup">o</span>P superior a 4 pontos &#40;NNT 28&#41; em compara&#231;&#227;o com os verificados na popula&#231;&#227;o total &#40;NNT 67 para os dois resultados cl&#237;nicos&#41;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">36&#44;47&#44;48</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Os ensaios SPIRE&#8208;1 e SPIRE&#8208;2 testaram o efeito do bococizumab um total de 27 438 doentes maioritariamente em preven&#231;&#227;o secund&#225;ria&#44; tendo o SPIRE&#8208;2 um limiar de elegibilidade para o c&#8208;LDL e c&#8208;n&#227;oHDL mais elevado &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a>&#46; Os dois estudos foram terminados precocemente por atenua&#231;&#227;o da efic&#225;cia hipolipemiante do bococizumab ao longo do tempo&#46; Ainda assim&#44; o bococizumab reduziu o risco relativo do resultado prim&#225;rio combinado de morte CV&#44; EM&#44; AVC ou AI com necessidade de revasculariza&#231;&#227;o urgente em 12&#37; e o resultado secund&#225;rio combinado de morte CV&#44; EM ou AVC em 13&#37;&#44; embora as diferen&#231;as n&#227;o tenham sido estatisticamente significativas&#46; No SPIRE 2&#44; em que a exposi&#231;&#227;o ao bococizumab foi mais prolongada e o c&#8208;LDL basal mais elevado&#44; observaram&#8208;se redu&#231;&#245;es estatisticamente significativas no risco relativo do resultado prim&#225;rio &#40;21&#37;&#41; e do secund&#225;rio &#40;26&#37;&#41;&#44; em compara&#231;&#227;o com o placebo&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Finalmente&#44; o ensaio cl&#237;nico ODISSEY&#8208;Outcomes incluiu 18 924 doentes com s&#237;ndroma coron&#225;ria aguda recente&#44; seguidos durante uma mediana de 2&#44;6 anos&#44; sob terap&#234;utica com estatina &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">13</span></a>&#46; O alirocumab reduziu significativamente o risco relativo do resultado prim&#225;rio combinado de morte de causa coron&#225;ria&#44; EM&#44; AVC ou AI em 15&#37; e do resultado secund&#225;rio combinado de morte de qualquer causa&#44; EM ou AVC em 14&#37;&#46; Ocorreram redu&#231;&#245;es significativas no risco relativo de EM n&#227;o fatal &#40;14&#37;&#41;&#44; AVC &#40;27&#37;&#41;&#44; AI &#40;39&#37;&#41; e RC &#40;12&#37;&#41;&#46; O alirocumab n&#227;o reduziu o risco de morte coron&#225;ria ou CV&#46; O benef&#237;cio foi consistente nas an&#225;lises de subgrupos&#46; Numa an&#225;lise <span class="elsevierStyleItalic">post hoc</span> observou&#8208;se uma redu&#231;&#227;o significativa de 28&#37; no risco relativo da morte coron&#225;ria e de 31&#37; na morte CV com o alirocumab <span class="elsevierStyleItalic">versus</span> placebo&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Em resumo&#44; no seu conjunto&#44; os estudos de eventos cardiovasculares com os anticorpos monoclonais anti&#8208;PCSK9 corroboram o conceito estabelecido da associa&#231;&#227;o linear entre o c&#8208;LDL obtido e a taxa de eventos CV&#44; independentemente do valor de LDL atingido&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Utiliza&#231;&#227;o de IPCSK9 na hipercolesterolemia familiar</span><p id="par0120" class="elsevierStylePara elsevierViewall">A hipercolesterolemia familiar associa&#8208;se a um risco acrescido de doen&#231;a cardiovascular numa fase prematura<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">49</span></a>&#46; &#201; sabido que indiv&#237;duos com valores c&#8208;LDL&#62;190<span class="elsevierStyleHsp" style=""></span>mg&#47;dL s&#227;o considerados de risco cardiovascular elevado<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">5</span></a> e que a sua maioria tem hipercolesterolemia familiar &#40;HF&#41;&#44; seja monog&#233;nica &#40;causada por muta&#231;&#245;es de genes envolvidos no metabolismo do c&#8208;LDL&#41; ou polig&#233;nica &#40;resultante da intera&#231;&#227;o de dieta aterog&#233;nica e m&#250;ltiplos fatores gen&#233;ticos mal definidos&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A popula&#231;&#227;o com HF &#233; bastante heterog&#233;nea devido ao n&#250;mero elevado de poss&#237;veis muta&#231;&#245;es causadoras de HF&#44; sendo que a extens&#227;o da doen&#231;a ateroscler&#243;tica e o risco cardiovascular dependem fundamentalmente dos n&#237;veis de c&#8208;LDL e do tempo de exposi&#231;&#227;o&#46; A causa mais frequente de hipercolesterolemia familiar monog&#233;nica &#233; a muta&#231;&#227;o do gene do r&#8208;LDL &#40;&#8764;90&#37;&#41;&#44; seguida de muta&#231;&#245;es do gene ApoB &#40;&#8764;5&#37;&#41;&#44; muta&#231;&#245;es com ganho de fun&#231;&#227;o do gene PCSK9 &#40;&#60;1&#37;&#41; e muito raramente muta&#231;&#245;es com perda de fun&#231;&#227;o do gene LDLRAP1 &#40;que codifica uma prote&#237;na que promove a internaliza&#231;&#227;o do complexo r&#8208;LDLR&#47;c&#8208;LDL&#41;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">50</span></a>&#46; A forma heterozig&#243;tica de HF &#40;HFHe&#41; tem uma preval&#234;ncia estimada de 1&#47;500 &#8208; 1&#47;200 na popula&#231;&#227;o geral sendo a forma homozig&#243;tica &#40;HFHo&#41; mais rara&#58; &#8764;1&#47;160 000 &#8208; 1&#47;300 000<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">42</span></a>&#46; A HF est&#225; subdiagnosticada particularmente a forma heterozig&#243;tica em que muitas vezes a suspeita s&#243; surge ap&#243;s um evento coron&#225;rio precoce &#40;idade &#60; 55 anos nos homens e &#60; 60 anos nas mulheres&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Tamb&#233;m na dislipidemia familiar a redu&#231;&#227;o dos valores de c&#8208;LDL reduz o risco de eventos CV&#46; Nestes doentes&#44; a preven&#231;&#227;o prim&#225;ria &#233; mais eficaz do que a preven&#231;&#227;o secund&#225;ria na redu&#231;&#227;o da mortalidade por doen&#231;a coron&#225;ria &#40;48&#37; <span class="elsevierStyleItalic">versus</span> 25&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">51</span></a>&#46; Em geral&#44; na dislipidemia familiar recomenda&#8208;se que o tratamento farmacol&#243;gico se dever&#225; iniciar o mais precocemente poss&#237;vel &#40;a partir dos 8&#8208;10 anos de idade&#41; para prevenir excesso de mortalidade em adultos&#46; Al&#233;m disso&#44; ultimamente tem&#8208;se debatido a estratifica&#231;&#227;o de risco CV dos doentes com HF&#44; numa tentativa de identificar precocemente os doentes de risco mais elevado&#44; em que se justifica uma terap&#234;utica hipolipemiante mais agressiva&#46; De acordo com as recomenda&#231;&#245;es europeias nos indiv&#237;duos adultos com HF&#44; sem doen&#231;a cardiovascular estabelecida&#44; o valor alvo de c&#8208;LDL deve ser &#60;100<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<span class="elsevierStyleSup">5</span>&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Os IPCSK9 foram testados em v&#225;rios estudos em indiv&#237;duos com HF&#46; O programa PROFICIO &#40;evolocumab&#41; incluiu doentes com HFHe &#40;RUTHERFORD&#8208;2&#41; e HFHo &#40;TESLA&#8208;A&#44;TESLA&#8208;B&#41;&#44; e est&#225; em curso o estudo TAUSSIG&#46; O programa ODYSSEY &#40;alirocumab&#41; incluiu apenas doentes com HFHe&#44; conforme detalhado na <a class="elsevierStyleCrossRef" href="#tbl0030">tabela 4</a><a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">42</span></a>&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">Estes estudos demonstraram a efic&#225;cia dos IPCSK9&#44; particularmente na HFHe&#44; permitindo redu&#231;&#227;o adicional de c&#8208;LDL &#8764;60&#37; em doentes com terap&#234;utica hipolipemiante m&#225;xima&#44; o que permite que 80&#37; destes doentes consiga atingir o valor alvo de c&#8208;LDL&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Outras formas de inibi&#231;&#227;o da PCSK9</span><p id="par0145" class="elsevierStylePara elsevierViewall">A terap&#234;utica com oligonucle&#243;tideos&#44; mol&#233;culas de cadeia simples ou dupla de DNA ou RNA com 10&#8208;50 nucleot&#237;deos&#44; an&#225;logos sint&#233;ticos de &#225;cidos nucleicos naturais&#44; &#233; um conceito emergente no tratamento das doen&#231;as cardiovasculares e do metabolismo lip&#237;dico&#46; Habitualmente&#44; este tipo de terap&#234;utica divide&#8208;se em dois grupos&#44; um&#44; constitu&#237;do pelos oligonucle&#243;tidos antisentido &#40;ASO&#41;&#44; as ribozimas e as pequenas mol&#233;culas de &#225;cido ribonucleico de interfer&#234;ncia &#40;siRNA&#44; que suprimem a express&#227;o de uma prote&#237;na por hibrida&#231;&#227;o com o ARN mensageiro alvo&#41; e um segundo grupo constitu&#237;do por apt&#226;meros que se ligam como anticorpos &#224;s prote&#237;nas alvo&#44; inibindo a sua fun&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">59</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">O inclisiran&#44; uma pequena cadeia &#250;nica de &#225;cido ribonucleico de interfer&#234;ncia&#44; &#233; a alternativa aos anticorpos monoclonais que se encontra em fase mais avan&#231;ada de desenvolvimento cl&#237;nico&#46; Este agente sint&#233;tico possui uma formula&#231;&#227;o com um ligando de N&#8208;acetilgalactosamina que permite a sua capta&#231;&#227;o hep&#225;tica&#44; e atua sinalizando o RNA mensageiro do PCSK9 para ser clivado o que condiciona a diminui&#231;&#227;o da sua s&#237;ntese<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">60</span></a>&#46; O efeito farmacodin&#226;mico &#233; prolongado o que permite a sua administra&#231;&#227;o parent&#233;rica semestral&#46; No estudo de fase II ORION&#8208;1&#44; a dose de 300<span class="elsevierStyleHsp" style=""></span>mg administrada por via subcut&#226;nea no in&#237;cio do estudo e aos tr&#234;s meses reduziu o C&#8208;LDL em 52&#44;6&#37;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">61</span></a>&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Seguran&#231;a dos anticorpos monoclonais da PCSK9</span><p id="par0155" class="elsevierStylePara elsevierViewall">No geral&#44; a utiliza&#231;&#227;o dos anticorpos monoclonais anti&#8208;PCSK9 revelou&#8208;se bastante segura nos estudos de eventos cardiovasculares &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 5</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">11&#8211;13</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">tabela 6</a>&#41;&#44; confirmando os dados dos estudos iniciais<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">36</span></a>&#46; A administra&#231;&#227;o destes agentes pode originar uma rea&#231;&#227;o local como eritema&#44; tumefa&#231;&#227;o ou prurido&#44; geralmente ligeira&#44; cuja incid&#234;ncia variou entre 2&#44;1&#37; e 10&#44;4&#37; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 5</a>&#41;&#46; Este valor mais elevado foi observado com o bococizumab e pode estar associado &#224; sua natureza parcialmente murina&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">N&#227;o se observou um aumento da incid&#234;ncia do diagn&#243;stico de diabetes <span class="elsevierStyleItalic">mellitus</span> de novo &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 5</a>&#41;&#44; contrariando a hip&#243;tese de que valores mais baixos de C&#8208;LDL poderem condicionar maior risco de diabetes<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">62</span></a>&#46; Este efeito neutro sobre o controlo glic&#233;mico foi confirmado numa suban&#225;lise do estudo FOURIER<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">63</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Tamb&#233;m n&#227;o se observou toxicidade hep&#225;tica ou muscular&#46; O desenvolvimento de anticorpos neutralizantes do dos mAb anti&#8208;PCSK9 foi descrito em 43 doentes sob alirocumab &#40;0&#44;5&#37;&#41; no ODISSEY&#8208;Outcomes mas n&#227;o foi documentado para o evolocumab no FOURIER&#46; Como j&#225; foi referido&#44; a dete&#231;&#227;o frequente de anticorpos neutralizantes para o bococizumab levou &#224; interrup&#231;&#227;o do seu programa de desenvolvimento cl&#237;nico&#46; As rea&#231;&#245;es adversas mais frequentes com o evolocumab foram a nasofaringite &#40;4&#44;8&#37;&#41; e infe&#231;&#227;o das vias respirat&#243;rias superiores &#40;3&#44;2&#37;&#41;&#44; a dorsalgia &#40;3&#44;1&#37;&#41; e a artralgia &#40;2&#44;2&#37;&#41;&#44; as s&#237;ndromes gripais &#40;2&#44;3&#37;&#41; e as n&#225;useas &#40;2&#44;1&#37;&#41;&#46; Com o alirocumab&#44; as rea&#231;&#245;es adversas mais frequentes foram as rea&#231;&#245;es locais no local da inje&#231;&#227;o &#40;<span class="elsevierStyleItalic">e&#46;g&#46;</span> eritema&#44; dor e hematoma no local da inje&#231;&#227;o&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Finalmente&#44; os receios de que valores muito baixos de c&#8208;LDL pudessem estar relacionados com disfun&#231;&#227;o cognitiva n&#227;o foram&#44; at&#233; &#224; data&#44; confirmados nos ensaios cl&#237;nicos&#46; No estudo EBBINGHAUS que avaliou espec&#237;fica e detalhadamente o desempenho neurocognitivo dos doentes sob evolocumab&#44; este foi sobrepon&#237;vel ao do placebo nas avalia&#231;&#245;es &#224;s 24 semanas e no final do ensaio cl&#237;nico<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">64</span></a>&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Apesar da excelente seguran&#231;a demonstrada pelos anticorpos monoclonais anti&#8208;PCSK9 a m&#233;dio prazo&#44; n&#227;o se conhecem os efeitos da exposi&#231;&#227;o prolongada a estes agentes&#46; As s&#237;ndromas gen&#233;ticas associadas &#224; hipocolesterolemia familiar&#44; em particular as originadas por muta&#231;&#245;es do PCSK9 com perda de fun&#231;&#227;o&#44; podem representar um modelo de exposi&#231;&#227;o prolongada aos anti&#8208;PCSK9<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">65</span></a>&#46; Nos portadores destas doen&#231;as n&#227;o est&#227;o descritos dist&#250;rbios neurocognitivos&#44; exceto numa muta&#231;&#227;o espec&#237;fica da ApoB &#40;isoforma truncada de ApoB29&#46;4&#41;&#46; Contudo&#44; o risco de esteatose hep&#225;tica &#233; elevado&#44; sendo superior a 70&#37; nos portadores de isoformas truncadas de ApoB100&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">An&#225;lises de custo&#8208;efetividade dos IPCSK9</span><p id="par0180" class="elsevierStylePara elsevierViewall">Apesar da efic&#225;cia dos IPCSK9 na redu&#231;&#227;o do risco de eventos cardiovasculares&#44; a sua utiliza&#231;&#227;o na pr&#225;tica cl&#237;nica tem sido relativamente baixa<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">66</span></a>&#44; sobretudo devido ao pre&#231;o do tratamento&#46; Mais do que o pre&#231;o&#44; hoje em dia &#233; essencial a avalia&#231;&#227;o da custo&#8208;efetividade da terap&#234;utica&#46; Em rela&#231;&#227;o aos IPCSK9&#44; existem v&#225;rios estudos de custo&#8208;efetividade publicados&#46; Os resultados destas an&#225;lises t&#234;m sido muito heterog&#233;neos&#44; com valores de ICER &#40;<span class="elsevierStyleItalic">incremental cost&#8208;effectiveness ratio</span>&#41; que variam entre os 30&#46;000&#8364; e os 166&#46;000&#8364; por QALY ganho<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">67</span></a> dependendo dos modelos de simula&#231;&#227;o&#44; do perfil de doentes inclu&#237;dos na an&#225;lise&#44; do contexto de utiliza&#231;&#227;o e do custo do tratamento&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Para melhorar a custo&#8208;efetividade destes f&#225;rmacos tem sido proposta uma estrat&#233;gia de &#171;m&#225;ximo risco&#47;m&#225;ximo benef&#237;cio&#187;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">68</span></a>&#46; Isto significa que a utiliza&#231;&#227;o destes f&#225;rmacos deve ser privilegiada nos doentes de &#171;m&#225;ximo risco&#187;&#44; nomeadamente aqueles com maior probabilidade de virem a ter um evento cardiovascular como aqueles com antecedentes de DCV &#43; atingimento multivascular ou diabetes&#46; Por outro lado&#44; tendo como premissa que a redu&#231;&#227;o do risco relativo em doentes com risco CV elevado &#233; proporcional &#224; diminui&#231;&#227;o absoluta do c&#8208;LDL e que a magnitude da redu&#231;&#227;o percentual de c&#8208;LDL com os IPCSK9 &#233; semelhante nos diferentes subgrupos de c&#8208;LDL basal&#44; os doentes com valores iniciais mais elevados de c&#8208;LDL ir&#227;o alcan&#231;ar a maior redu&#231;&#227;o absoluta no c&#8208;LDL e&#44; consequente&#44; uma redu&#231;&#227;o mais significativa do risco CV &#40;&#171;m&#225;ximo benef&#237;cio&#187;&#41;&#46; &#201; com base neste conceito que&#44; nestas recomenda&#231;&#245;es&#44; prop&#245;e&#8208;se uma utiliza&#231;&#227;o preferencial nos grupos de doentes que mais podem beneficiar da terap&#234;utica atendendo&#44; simultaneamente&#44; ao risco CV do doente e o valor absoluto de c&#8208;LDL&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Relativamente &#224;s an&#225;lises de custo&#8208;efetividade na realidade portuguesa&#44; apesar dos dados n&#227;o serem conhecidos&#44; em 28 de dezembro de 2018&#44; o INFARMED apresentou o Relat&#243;rio P&#250;blico de Avalia&#231;&#227;o Pr&#233;via do Medicamento em Meio Hospitalar respeitante ao evolocumab&#44; que considera que &#171;os valores de custo&#8208;efetividade incrementais associados &#224; introdu&#231;&#227;o do evolucomab no arsenal terap&#234;utico&#44; assim como os resultados do impacto or&#231;amental&#44; foram considerados aceit&#225;veis&#187;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">69</span></a>&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Recomenda&#231;&#245;es para a utiliza&#231;&#227;o dos IPCSK9</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Utiliza&#231;&#227;o dos IiPCSK9 em preven&#231;&#227;o secund&#225;ria</span><p id="par0195" class="elsevierStylePara elsevierViewall">Os doentes com DCV estabelecida e&#44; em particular&#44; os que j&#225; tiveram um evento de natureza aterotromb&#243;tica&#44; s&#227;o aqueles que apresentam maior risco de recorr&#234;ncia de eventos CV<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">70</span></a>&#46; Dada a associa&#231;&#227;o entre os valores de c&#8208;LDL e o risco de eventos&#44; os objetivos terap&#234;uticos recomendados de c&#8208;LDL para estes doentes s&#227;o particularmente restritivos&#44; sendo desej&#225;vel atingir c&#8208;LDL &#60;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dl<span class="elsevierStyleSup">5</span>&#44; mas reconhecendo&#8208;se que h&#225; subgrupos de &#171;risco extremo&#187;&#44; que poder&#227;o beneficiar de valores ainda mais baixos&#44; nomeadamente &#60; 55<span class="elsevierStyleHsp" style=""></span>mg&#47;dl<span class="elsevierStyleSup">7</span>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Nestes doentes&#44; o primeiro passo na terap&#234;utica deve ser a utiliza&#231;&#227;o de estatina de alta intensidade&#44; nomeadamente atorvastatina 40&#8208;80<span class="elsevierStyleHsp" style=""></span>mg ou rosuvastatina 20&#8208;40<span class="elsevierStyleHsp" style=""></span>mg&#44; a que se associa um aconselhamento nutricional adequado e o cumprimento adequado das medidas de estilo de vida&#46; Segundo alguns modelos de simula&#231;&#227;o publicados&#44; estima&#8208;se que 32&#37; dos doentes n&#227;o v&#227;o atingir o valor alvo apenas com estatina de alta intensidade&#44; sendo necess&#225;rio recorrer a associa&#231;&#245;es de antidislipid&#233;micos<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">71</span></a>&#46; Deste modo&#44; o passo seguinte &#233; considerar a associa&#231;&#227;o de ezetimiba que&#44; pelo seu custo e boa tolerabilidade&#44; permite uma redu&#231;&#227;o adicional de c&#8208;LDL<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">72</span></a> e desse modo cerca de mais 19&#37; dos doentes atingir&#227;o o valor de c&#8208;LDL desejado de acordo com a mesma an&#225;lise&#46; Ainda assim&#44; h&#225; cerca de 14&#37; que ir&#227;o manter valores de c&#8208;LDL acima do desej&#225;vel&#44; para os quais dever&#225; ser considerada a terap&#234;utica com IPCSK9&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">A utiliza&#231;&#227;o racional destes f&#225;rmacos passa pela identifica&#231;&#227;o de grupos de maior risco absoluto e com valor de c&#8208;LDL mais elevado&#44; nos quais o benef&#237;cio esperado &#233; maior&#46; Esta tem sido a postura da maioria das recomenda&#231;&#245;es j&#225; publicadas sobre a utiliza&#231;&#227;o dos IPCSK9&#44; conforme detalhado na <a class="elsevierStyleCrossRef" href="#tbl0020">tabela 5</a>&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">O <span class="elsevierStyleItalic">National Institute for Health and Care Excellence</span> &#40;NICE&#41;&#44; em 2016&#44; emitiu recomenda&#231;&#245;es para a sua utiliza&#231;&#227;o em doentes com doen&#231;a cardiovascular estabelecida se os valores de c&#8208;LDL&#62; 150<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e alto risco &#40;SCA&#44; AVC isqu&#233;mico&#44; procedimento de revasculariza&#231;&#227;o coron&#225;ria ou arterial&#44; doen&#231;a coron&#225;ria ou doen&#231;a arterial perif&#233;rica&#41; ou &#62; 130<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e muito alto risco &#40;doen&#231;a polivascular ou eventos CV recorrentes&#41;&#46; O &#250;nico cen&#225;rio em que foi considerada a terap&#234;utica em preven&#231;&#227;o prim&#225;ria foi a com HeHF se c&#8208;LDL &#62; 190<span class="elsevierStyleHsp" style=""></span>mg&#47;dl<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">73</span></a>&#46; A Sociedade Espanhola de Cardiologia &#40;SEC&#41; considera a utiliza&#231;&#227;o destes f&#225;rmacos em doentes em preven&#231;&#227;o secund&#225;ria que tenham cardiopatia isqu&#233;mica e c&#8208;LDL &#62; 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl apesar de tratamento otimizado e em doentes com c&#8208;LDL&#62; 70<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e SCA recorrente ou cardiopatia isqu&#233;mica e hipercolesterolemia familiar<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">74</span></a>&#46; Al&#233;m disso&#44; &#233; recomendada a utiliza&#231;&#227;o de IPCSK9 nos doentes com cardiopatia isqu&#233;mica e intoler&#226;ncia comprovada &#224;s estatinas e ainda nos doentes que apesar de n&#227;o terem doen&#231;a cardiovascular conhecida tenham c&#8208;LDL &#62; 130<span class="elsevierStyleHsp" style=""></span>mg&#47;dL e diabetes &#40;tipo 1 ou 2&#41; com les&#227;o de &#243;rg&#227;o alvo &#40;LOA&#41;&#44; doen&#231;a renal cr&#243;nica &#40;DRC&#41; com TFG &#60; 60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#44;73 m2 ou SCORE&#62; 10&#37;&#46; A <span class="elsevierStyleItalic">Task Force</span> da Sociedade Europeia de Cardiologia &#40;ESC&#41; e a Sociedade Europeia de Aterosclerose &#40;ESA&#41; prop&#245;e como candidatos a esta terap&#234;utica os doentes com muito alto risco cardiovascular&#44; incluindo os doentes com evid&#234;ncia cl&#237;nica ou imagiol&#243;gica de doen&#231;a ateroscler&#243;tica que&#44; apesar de dose m&#225;xima de estatina&#44; e ap&#243;s associa&#231;&#227;o de ezetimiba&#44; t&#234;m c&#8208;LDL &#62; 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dl ou &#62; 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl se evid&#234;ncia de r&#225;pida progress&#227;o da doen&#231;a &#40;definida como recorr&#234;ncia de SCA&#44; revasculariza&#231;&#227;o n&#227;o programada ou AVC nos 5 anos ap&#243;s o evento &#237;ndex&#41;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">75</span></a>&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">As recomenda&#231;&#245;es do consenso de peritos do <span class="elsevierStyleItalic">American College of Cardiology</span> &#40;ACC&#41; sobre o uso de antidislipid&#233;micos que n&#227;o estatinas s&#227;o mais abrangentes&#44; definindo que se deve considerar a associa&#231;&#227;o de ezetimiba ou inibidor PCSK9 na preven&#231;&#227;o secund&#225;ria em doentes com doen&#231;a ateroscler&#243;tica estabelecida se n&#227;o tiver sido atingido o objetivo de redu&#231;&#227;o de &#8805; 50&#37; &#40;considerar c&#8208;LDL&#60; 70<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41; sob a dose m&#225;xima tolerada de estatina&#46; Para os doentes sem comorbilidades associadas&#44; a adi&#231;&#227;o de ezetimiba deve ser o primeiro passo&#46; Contudo&#44; nos doentes com um fator multiplicador de risco &#40;como diabetes&#44; doen&#231;a renal cr&#243;nica&#44; evento cardiovascular sob estatina&#44; AVC isqu&#233;mico ou EAM pr&#233;vio&#44; &#8805;65 anos&#41; o inibidor PCSK9 deve ser preferido ao ezetimiba se a redu&#231;&#227;o adicional pretendida for &#62;25&#37;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">76</span></a>&#46; Mais recentemente as recomenda&#231;&#245;es americanas para a abordagem da hipercolesterolemia refor&#231;am o conceito de otimiza&#231;&#227;o terap&#234;utica inicial com ezetimiba antes de considerar o IPCSK9&#44; acrescentando ainda uma nova recomenda&#231;&#227;o de valor relacionada com a an&#225;lise de custo&#8208;efectividade para estes f&#225;rmacos&#44; os quais&#44; para os valores de 2018 praticados nos EUA&#44; s&#227;o pouco custo&#8208;eficazes<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">14</span></a>&#46; Esta reflex&#227;o&#44; que n&#227;o questiona os resultados dos ensaios cl&#237;nicos&#44; mas faz uma an&#225;lise sobre a sua utilidade nos ganhos em sa&#250;de&#44; vai largamente depender do custo do f&#225;rmaco em cada pa&#237;s e daquilo que &#233; considerado aceit&#225;vel por cada sistema de sa&#250;de a n&#237;vel nacional&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Recomenda&#231;&#245;es do painel para Portugal</span><p id="par0220" class="elsevierStylePara elsevierViewall">Depois de analisada a evid&#234;ncia cl&#237;nica&#44; as an&#225;lises de custo&#8208;efetividade e as recomenda&#231;&#245;es emitidas por outras sociedades cient&#237;ficas&#44; os autores prop&#245;em que se considere a associa&#231;&#227;o de um IPCSK9 nos doentes com terap&#234;utica anti&#8208;dislipid&#233;mica otimizada que tenham tido evento aterotromb&#243;tico pr&#233;vio e tenham&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Valor c&#8208;LDL <span class="elsevierStyleItalic">&#8805;</span> 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dl</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Valor c&#8208;LDL <span class="elsevierStyleItalic">&#8805;</span> 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e um dos seguintes fatores&#58;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8208;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Diabetes com les&#227;o de &#243;rg&#227;o&#8208;alvo &#40;exemplo&#44; protein&#250;ria&#41;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8208;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Doen&#231;a polivascular</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8208;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Doen&#231;a coron&#225;ria significativa multivaso&#44; revascularizada ou n&#227;o</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8208;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Evento cardiovascular recorrente &#40;&#60;5 anos ap&#243;s primeiro evento&#41;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8208;</span><p id="par0255" class="elsevierStylePara elsevierViewall">Hipercolesterolemia familiar</p></li></ul></p><p id="par0260" class="elsevierStylePara elsevierViewall">Antes de se considerar a introdu&#231;&#227;o de IPCSK9 devem verificar&#8208;se &#40;todas&#41; as seguintes condi&#231;&#245;es&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8208;</span><p id="par0265" class="elsevierStylePara elsevierViewall">Tratamento com a dose m&#225;xima tolerada de estatina de alta intensidade &#40;atorvastatina 40&#8208;80<span class="elsevierStyleHsp" style=""></span>mg ou rosuvastatina 20&#8208;40<span class="elsevierStyleHsp" style=""></span>mg&#41;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8208;</span><p id="par0270" class="elsevierStylePara elsevierViewall">Tratamento de associa&#231;&#227;o com ezetimiba 10<span class="elsevierStyleHsp" style=""></span>mg</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8208;</span><p id="par0275" class="elsevierStylePara elsevierViewall">Adequado controlo dos restantes fatores de risco</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8208;</span><p id="par0280" class="elsevierStylePara elsevierViewall">Implementa&#231;&#227;o de altera&#231;&#227;o do estilo de vida&#44; incluindo aconselhamento nutricional e cessa&#231;&#227;o tab&#225;gica &#40;<a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a>&#41;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></li></ul></p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Utiliza&#231;&#227;o dos IPCSK9 na hipercolesterolemia familiar&#44; sem doen&#231;a cardiovascular conhecida</span><p id="par0285" class="elsevierStylePara elsevierViewall">As recomenda&#231;&#245;es da ESC&#47;EAS sobre o uso de IPCSK9 aconselham a sua utiliza&#231;&#227;o em doentes com HeHF sem doen&#231;a cardiovascular estabelecida&#44; de risco CV alto ou muito alto&#44; se tiverem n&#237;veis de c&#8208;LDL &#62; 180<span class="elsevierStyleHsp" style=""></span>mg&#47;dL ap&#243;s a otimiza&#231;&#227;o da terap&#234;utica hipolipemiante<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">77</span></a>&#46; Aconselham ainda que na presen&#231;a de fatores de risco adicionais &#40;diabetes&#44; n&#237;veis elevados de Lp&#40;a&#41;&#44; DCV prematura em familiar de primeiro grau&#44; tabagismo&#44; indicadores de gravidade por imagem&#41; o valor de c&#8208;LDL para se considerar a introdu&#231;&#227;o de IPCSK9 deve ser mais baixo &#40;&#62; 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">Em doentes com HFHo os IPCSK9 s&#227;o recomendados como terap&#234;utica adicional para reduzir os n&#237;veis de c&#8208;LDL&#44; em doentes a fazer ou n&#227;o af&#233;rese das LDL&#46; Por outro lado&#44; em doentes com muta&#231;&#245;es negativa&#47;negativa do r&#8208;LDL&#44; que t&#234;m uma atividade de r&#8208;LDL inferior a 2&#37; n&#227;o se recomenda IPCSK9&#44; porque o seu mecanismo de a&#231;&#227;o implica algum n&#237;vel de atividade do r&#8208;LDL<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">44&#44;54</span></a>&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Recomenda&#231;&#245;es do painel para Portugal</span><p id="par0295" class="elsevierStylePara elsevierViewall">Na hipercolesterolemia familiar&#44; sem evento cardiovascular pr&#233;vio&#44; prop&#245;em&#8208;se que se considere a associa&#231;&#227;o de um iPCSK9 nos doentes que&#44; ap&#243;s terap&#234;utica hipolipemiante otimizada&#44; mantenham&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">1&#46;</span><p id="par0300" class="elsevierStylePara elsevierViewall">Valor c&#8208;LDL &#8805; 180<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#59;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">2&#46;</span><p id="par0305" class="elsevierStylePara elsevierViewall">Valor c&#8208;LDL &#8805; 140<span class="elsevierStyleHsp" style=""></span>mg&#47;dl e um dos seguintes fatores&#58;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8208;</span><p id="par0310" class="elsevierStylePara elsevierViewall">Diabetes com les&#227;o de &#243;rg&#227;o&#8208;alvo &#40;ex&#46; protein&#250;ria&#41; ou 1 fator de risco <span class="elsevierStyleItalic">major</span></p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8208;</span><p id="par0315" class="elsevierStylePara elsevierViewall">Lipoprote&#237;na &#40;a&#41; &#62; 50<span class="elsevierStyleHsp" style=""></span>mg&#47;dL</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8208;</span><p id="par0320" class="elsevierStylePara elsevierViewall">Fatores de risco <span class="elsevierStyleItalic">major</span>&#58; exemplo&#44; hipertens&#227;o arterial estadio 2 e 3 &#40;PA &#62; 160&#47;100<span class="elsevierStyleHsp" style=""></span>mmHg&#41; n&#227;o controlada</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8208;</span><p id="par0325" class="elsevierStylePara elsevierViewall">Doen&#231;a cardiovascular prematura em familiar 1&#176; grau &#40;homem &#60; 55 anos&#59; mulher &#60; 60 anos&#41;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8208;</span><p id="par0330" class="elsevierStylePara elsevierViewall">Doen&#231;a ateroscler&#243;tica subcl&#237;nica significativa</p></li></ul></p><p id="par0335" class="elsevierStylePara elsevierViewall">Uma vez mais&#44; antes de se considerar a introdu&#231;&#227;o de iPCSK9 devem verificar&#8208;se &#40;todas&#41; as seguintes condi&#231;&#245;es&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8208;</span><p id="par0340" class="elsevierStylePara elsevierViewall">Tratamento com a dose m&#225;xima tolerada de estatina de alta intensidade &#40;atorvastatina 40&#8208;80<span class="elsevierStyleHsp" style=""></span>mg ou rosuvastatina 20&#8208;40<span class="elsevierStyleHsp" style=""></span>mg&#41;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8208;</span><p id="par0345" class="elsevierStylePara elsevierViewall">Tratamento de associa&#231;&#227;o com ezetimiba 10<span class="elsevierStyleHsp" style=""></span>mg</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8208;</span><p id="par0350" class="elsevierStylePara elsevierViewall">Adequado controlo dos restantes fatores de risco cardiovascular</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8208;</span><p id="par0355" class="elsevierStylePara elsevierViewall">Implementa&#231;&#227;o de altera&#231;&#227;o do estilo de vida&#44; incluindo aconselhamento nutricional espec&#237;fico e cessa&#231;&#227;o tab&#225;gica &#40;<a class="elsevierStyleCrossRef" href="#fig0015">figura 3</a>&#41;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></li></ul></p><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Recomenda&#231;&#245;es para a utiliza&#231;&#227;o de iPCSK9 em doentes com intoler&#226;ncia &#224;s estatinas</span><p id="par0360" class="elsevierStylePara elsevierViewall">A maioria dos casos de intoler&#226;ncia &#224; estatina est&#225; diretamente relacionada com queixas subjetivas do doente&#44; sendo as altera&#231;&#245;es laboratoriais &#8211; como causa de descontinua&#231;&#227;o do tratamento &#8208; uma situa&#231;&#227;o menos comum&#46; Assim&#44; na maioria dos casos&#44; a intoler&#226;ncia &#224; estatina n&#227;o deve ser pontuada pela simples ocorr&#234;ncia de sintomas em geral&#44; mas pela presen&#231;a de sintomas percebidos como inaceit&#225;veis&#46; Sendo assim&#44; intoler&#226;ncia &#224; estatina deve ser entendida como uma s&#237;ndrome apurada&#44; atestada e documentada que leva a uma dosagem n&#227;o ideal de estatinas&#44; a menor ader&#234;ncia ao tratamento&#44; a diminui&#231;&#227;o da qualidade de vida do doente&#44; ou &#224; cessa&#231;&#227;o da estatina<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">78&#44;79</span></a>&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">N&#227;o existe uma defini&#231;&#227;o universalmente aceite de intoler&#226;ncia &#224; estatina&#44; mas existem v&#225;rios documentos que procuraram um consenso &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Tabela 1&#44; Suplemento</a>&#41;&#46; Comummente&#44; a intoler&#226;ncia &#224; estatina &#233; tida como a ocorr&#234;ncia de sintomas adversos &#40;quase sempre m&#250;sculo&#8208;esquel&#233;ticos&#41; percebidos como intoler&#225;veis pelo doente e&#47;ou pela presen&#231;a de altera&#231;&#245;es laboratoriais sugestivos de risco indevido &#40;<span class="elsevierStyleItalic">e&#46;g&#46;</span> CK&#44; ALT&#47;AST ou bilirrubina&#41;&#44; atribu&#237;veis ao tratamento com estatinas e que levam &#224; descontinua&#231;&#227;o do tratamento &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Tabela 2&#44; Suplement</a>o&#41;&#46; Na pr&#225;tica&#44; &#233; necess&#225;rio definir melhor a aceitabilidade dos sintomas&#44; a atribui&#231;&#227;o de uma presum&#237;vel causalidade e o grau de real intoler&#226;ncia&#46; Muito frequentemente &#8211; mesmo quando ocorrem durante o tratamento com uma estatina &#8211; os efeitos adversos musculares &#40;ou outros&#41; n&#227;o est&#227;o&#44; de facto&#44; relacionados com o f&#225;rmaco e a larga maioria destes doentes s&#227;o capazes de tolerar o tratamento adequado&#46; Esta identifica&#231;&#227;o dos falsos casos de intoler&#226;ncia &#224;s estatinas &#233; fundamental para evitar a descontinua&#231;&#227;o intempestiva&#44; desnecess&#225;ria e imprudente das estatinas em doentes que delas necessitam<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">80</span></a>&#46; Existem caracter&#237;sticas que ajudam o cl&#237;nico a identificar a maior ou menor probabilidade de causalidade dos sintomas com a toma de estatinas &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Tabela 3&#44; Suplemento</a>&#41;&#44; podendo tamb&#233;m ser utilizado o aplicativo <span class="elsevierStyleItalic">ACC Statin Intolerance</span> ou <span class="elsevierStyleItalic">scores</span> de probabilidade<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">81</span></a>&#46; Al&#233;m disso&#44; deve&#8208;se estar atento a fatores favorecedores de maior risco de intoler&#226;ncia &#224;s estatinas ou capazes de desencadear as manifesta&#231;&#245;es sintom&#225;ticas&#44; que devem ser tamb&#233;m avaliados &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Tabela 4&#44; Suplemento</a>&#41;&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall">Face &#224; grande varia&#231;&#227;o dos doentes em rela&#231;&#227;o ao n&#250;mero e &#224; dosagem de estatinas que s&#227;o incapazes de tolerar&#44; do ponto de vista pr&#225;tico&#44; podem&#8208;se ponderar dois graus de intoler&#226;ncia &#224;s estatinas&#58; &#40;1&#41; <span class="elsevierStyleItalic">a intoler&#226;ncia completa &#224; estatina</span> assente na incapacidade de tolerar um m&#237;nimo de tr&#234;s estatinas &#40;ainda que na menor dose di&#225;ria&#58; atorvastatina 10<span class="elsevierStyleHsp" style=""></span>mg&#44; fluvastatina 40<span class="elsevierStyleHsp" style=""></span>mg&#44; lovastatina 20<span class="elsevierStyleHsp" style=""></span>mg&#44; pitavastatina 2<span class="elsevierStyleHsp" style=""></span>mg&#44; pravastatina 40<span class="elsevierStyleHsp" style=""></span>mg&#44; rosuvastatina 5<span class="elsevierStyleHsp" style=""></span>mg e sinvastatina 20<span class="elsevierStyleHsp" style=""></span>mg&#41;&#59; e &#40;2&#41; <span class="elsevierStyleItalic">a intoler&#226;ncia parcial &#224;s estatinas</span> definida pela impossibilidade de tolerar a estatina na posologia necess&#225;ria ao atingimento do objetivo terap&#234;utico pretendido&#46; Esta &#250;ltima deve ser entendida&#44; de forma pragm&#225;tica&#44; de acordo com as necessidades terap&#234;uticas e os objetivos apontados em cada doente&#44; de modo que a intoler&#226;ncia a algumas estatinas &#40;ou a determinada posologia&#41; n&#227;o deve ser imprudentemente tida como intoler&#226;ncia &#224; estatina&#44; desde que n&#227;o interfira com o atingimento dos objetivos terap&#234;uticos&#46;</p><p id="par0375" class="elsevierStylePara elsevierViewall">Apesar da utiliza&#231;&#227;o de IPCSK9 em doentes intoler&#226;ncia &#224;s estatinas ser l&#243;gica e consensual&#44; esta n&#227;o &#233; indica&#231;&#227;o formalmente aprovada nas atuais indica&#231;&#245;es para a utiliza&#231;&#227;o dos iPCSK9<span class="elsevierStyleHsp" style=""></span>da EMEA&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Recomenda&#231;&#245;es do painel</span><p id="par0380" class="elsevierStylePara elsevierViewall">Em resumo&#44; a administra&#231;&#227;o de iPCSK9 deve ser considerada nos doentes incapazes de tolerar o tratamento com doses apropriadas de&#44; pelo menos&#44; tr&#234;s estatinas&#44; especialmente se coexistirem outros &#237;ndices de gravidade acrescida &#40;<span class="elsevierStyleItalic">e&#46;g&#46;</span> hipercolesterolemia familiar&#44; doen&#231;a polivascular ou multivasos ou doen&#231;a cardiovascular de natureza ateroscler&#243;tica rapidamente progressiva&#41;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">77</span></a>&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Gest&#227;o cl&#237;nica do doente sob terap&#234;utica com iPCSK9</span><p id="par0385" class="elsevierStylePara elsevierViewall">Os iPCSK9 devem ser prescritos em consulta hospitalar dedicada &#224; gest&#227;o de risco CV sob a coordena&#231;&#227;o de especialidades m&#233;dicas hospitalares&#46; Esta consulta deve ser baseada em protocolos de diagn&#243;stico e tratamento pr&#233;&#8208;estabelecidos&#44; elaborados por uma equipa multidisciplinar&#46;</p><p id="par0390" class="elsevierStylePara elsevierViewall">A elegibilidade para a eventual terap&#234;utica com iPCSK9 deve ser avaliada ap&#243;s otimiza&#231;&#227;o da terap&#234;utica farmacol&#243;gica com estatina na dose m&#225;xima tolerada e ezetimiba&#44; mas tamb&#233;m ap&#243;s otimiza&#231;&#227;o da terap&#234;utica n&#227;o farmacol&#243;gica&#44; com particular &#234;nfase na dieta orientada por nutricionista e controlo de outros fatores de risco CV&#44; incluindo o tabagismo <a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">6&#44;77</span></a>&#46; A avalia&#231;&#227;o para terap&#234;utica com iPCSK9 deve incluir a confirma&#231;&#227;o de ades&#227;o ao tratamento com estatina na dose m&#225;xima tolerada e ezetimiba&#44; podendo ser necess&#225;rio reavaliar o perfil lip&#237;dico ap&#243;s um per&#237;odo de quatro semanas com ades&#227;o plena&#44; se apropriado&#46; Recomenda&#8208;se ainda a avalia&#231;&#227;o da fun&#231;&#227;o renal e hep&#225;tica antes do in&#237;cio do tratamento&#46;</p><p id="par0395" class="elsevierStylePara elsevierViewall">O in&#237;cio do tratamento com um iPCSK9 constitui uma oportunidade para a implementa&#231;&#227;o de um programa de ensino multidisciplinar e estruturado ao doente&#44; visando a doen&#231;a ateroscler&#243;tica e a terap&#234;utica espec&#237;fica&#44; com eventual recurso a material multim&#233;dia e did&#225;tico&#46;</p><p id="par0400" class="elsevierStylePara elsevierViewall">A administra&#231;&#227;o inicial do anticorpo monoclonal anti&#8208;PCSK9 deve ser efetuada em ambiente hospitalar&#44; seguida de vigil&#226;ncia durante um per&#237;odo de 30 minutos&#46; As administra&#231;&#245;es seguintes poder&#227;o ser efetuadas no domic&#237;lio&#44; ap&#243;s o ensino do doente ou do seu cuidador&#46;</p><p id="par0405" class="elsevierStylePara elsevierViewall">O efeito hipolipemiante da terap&#234;utica deve ser avaliado cerca de quatro semanas ap&#243;s o in&#237;cio do tratamento&#46; No caso de o doente ser hiporrespondedor &#40;redu&#231;&#227;o do c&#8208;LDL&#60;25&#37;&#41; deve ser considerada a descontinua&#231;&#227;o da terap&#234;utica&#46; Nos indiv&#237;duos que atinjam valores de c&#8208;LDL&#60;25<span class="elsevierStyleHsp" style=""></span>mg&#47;dl deve ser considerada a redu&#231;&#227;o da dose<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">13</span></a>&#46;</p><p id="par0410" class="elsevierStylePara elsevierViewall">A monitoriza&#231;&#227;o do efeito hipolipemiante deve ser mantida com uma periodicidade pelo menos semestral e os efeitos adversos devem ser reportados ao Sistema Nacional de Farmacovigil&#226;ncia &#40;<a class="elsevierStyleCrossRef" href="#fig0020">figura 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclus&#227;o</span><p id="par0415" class="elsevierStylePara elsevierViewall">Os iPCSK9 s&#227;o uma nova op&#231;&#227;o terap&#234;utica que permite uma redu&#231;&#227;o significativa dos valores de c&#8208;LDL e do risco de eventos CV&#44; em doentes j&#225; medicados com terap&#234;utica hipolipemiante otimizada&#46;</p><p id="par0420" class="elsevierStylePara elsevierViewall">Estas recomenda&#231;&#245;es para a utiliza&#231;&#227;o dos iPCSK9 na pr&#225;tica cl&#237;nica em Portugal&#44; s&#227;o o resultado de uma reflex&#227;o multidisciplinar&#44; tentando integrar uma estrat&#233;gia de privilegiar a sua administra&#231;&#227;o aos doentes que mais possam beneficiar&#44; ou seja&#44; aqueles que t&#234;m simultaneamente maior risco e valores absolutos de c&#8208;LDL mais elevados&#46; Como com todas as recomenda&#231;&#245;es&#44; a sua aplica&#231;&#227;o na pr&#225;tica cl&#237;nica n&#227;o substitui a avalia&#231;&#227;o cl&#237;nica individual de cada doente&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflits of interst</span><p id="par0425" class="elsevierStylePara elsevierViewall">RFC received advisory or speaker fees from MSD&#44; Bial and Amgen&#46;</p><p id="par0430" class="elsevierStylePara elsevierViewall">PMS has received advisory or speaker fees from Bayer&#44; JABA&#8208;Recordati&#44; MSD Portugal&#44; Kowa Pharmaceuticals&#44; Novartis&#44; Daiichi Sankyo&#44; Amgen&#44; Sanofi&#8208;Regeneron e Tecnimede&#46;</p><p id="par0435" class="elsevierStylePara elsevierViewall">FA reports no conflts of interest&#46;</p><p id="par0440" class="elsevierStylePara elsevierViewall">CG received advisory or speaker fees from MSD&#44; Amgen&#46;</p><p id="par0445" class="elsevierStylePara elsevierViewall">JF has received advisory fees from Amgen&#46;</p><p id="par0450" class="elsevierStylePara elsevierViewall">JM has received advisory or speaker fees from Astra Zeneca&#44; Amgen&#44; Bayer&#44; Boehringer Ingelheim&#44; Jaba&#44; Servier&#44; Novartis&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A redu&#231;&#227;o dos valores de c&#8208;LDL &#233; uma das estrat&#233;gias mais importantes para a redu&#231;&#227;o do risco de eventos cardiovasculares&#46; Contudo&#44; na pr&#225;tica cl&#237;nica&#44; um grande n&#250;mero de doentes n&#227;o atinge os valores recomendados de c&#8208;LDL com a modifica&#231;&#227;o do estilo de vida e a terap&#234;utica hipolipemiante com estatinas e ezetimiba&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Os f&#225;rmacos inibidores da PCSK9 &#40;iPCSK9&#41; s&#227;o uma nova op&#231;&#227;o terap&#234;utica que permite uma redu&#231;&#227;o significativa dos valores de c&#8208;LDL &#40;50&#8208;60&#37;&#41;&#44; que se traduziu nos ensaios cl&#237;nicos numa redu&#231;&#227;o adicional do risco de eventos cardiovasculares&#44; com bom perfil de seguran&#231;a&#46; Por&#233;m&#44; &#233; uma terap&#234;utica com custos elevados&#44; pelo que a utiliza&#231;&#227;o na pr&#225;tica cl&#237;nica deve ter em conta a sua custo&#8208;efetividade devendo ser dada prioridade &#224; utiliza&#231;&#227;o nos doentes de maior risco cardiovascular e que mant&#234;m valores elevados de c&#8208;LDL apesar da terap&#234;utica hipolipemiante otimizada&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Este documento de consenso&#44; tem como objetivo resumir os principais dados sobre a utiliza&#231;&#227;o cl&#237;nica dos iPCSK9 e estabelecer recomenda&#231;&#245;es para Portugal sobre o perfil de doentes que mais pode beneficiar desta terap&#234;utica&#46;</p></span>"
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                  \t\t\t\t">Alirocumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">ODYSSEY&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SPIRE&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Aprova&#231;&#227;o pela EMA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMS&#8208;84442&#44; SPC5001&#44; SPC4061&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fase I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Descontinuados&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Pequenas mol&#233;culas inibidoras da PCSK9</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Adnectina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMS&#8208;962476&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fase I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anexina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anexina A2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pr&#233;&#8208;cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Vacina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AT04A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pr&#233;&#8208;Cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Diferentes formas de inibi&#231;&#227;o da PCSK9</p>"
        ]
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      5 => array:8 [
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">TG&#58; Triglicer&#237;deos&#59; Lp&#40;a&#41;&#58; lipoprote&#237;na &#40;a&#41;&#59; ApoB&#58; Apolipoprote&#237;na B</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Colesterol total&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">C&#8208;LDL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Lp&#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ApoB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alirocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;39&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;60&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-6&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;9&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;26&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;50&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bococizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;34&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;57&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-6&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;14&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;24&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;46&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evolocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;42&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;71&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-12&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;17&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;45&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208;56&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Diferen&#231;a na varia&#231;&#227;o percentual dos par&#226;metros lip&#237;dicos&#44; entre os AM anti&#8208;PCSK9 e placebo &#224;s 12&#47;24 semanas&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">34&#44;35</span></a></p>"
        ]
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Os valores dos par&#226;metros lip&#237;dicos s&#227;o expressos em mg&#47;dl&#46; ApoB&#58; Apolipoprote&#237;na B&#59; AVC&#58; Acidente vascular cerebral&#59; C&#8208;LDL&#58; Colesterol das lipoprote&#237;nas de baixa densidade &#40;mg&#47;dl&#41;&#59; C&#8208;n&#227;oHDL&#58; Colesterol das lipoprote&#237;nas n&#227;o alta densidade &#40;mg&#47;dl&#41; CV&#58; Cardiovascular&#59; DAP&#58; Doen&#231;a arterial perif&#233;rica&#59; EM&#58; Enfarte do mioc&#225;rdio&#59; SCA&#58; s&#237;ndroma coron&#225;ria aguda&#59; Sem&#58; Semanas&#59; 1<span class="elsevierStyleHsp" style=""></span>&#170;&#58; Prim&#225;ria&#59; 2<span class="elsevierStyleHsp" style=""></span>&#170;&#58; Secund&#225;ria&#59;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ODISSEY Outcomes<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SPIRE&#8208;1<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SPIRE&#8208;2<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FOURIER<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Agente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alirocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bococizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evolocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">75 ou 150<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem &#40;ajustado para atingir c&#8208;LDL alvo 25&#8208;50mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">150<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem&#40;reduzido para 75<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem se c&#8208;LDL&#60;10&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">140<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem ou420<span class="elsevierStyleHsp" style=""></span>mg 4&#47;4 sem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#250;mero de doentes inclu&#237;dos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18924&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16817&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10621&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27564&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Popula&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SCA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Preven&#231;&#227;o 2<span class="elsevierStyleHsp" style=""></span>&#170; &#40;84&#37;&#41; ou1<span class="elsevierStyleHsp" style=""></span>&#170; com risco CV elevado &#40;16&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EAM &#40;81&#37;&#41;&#44; AVC &#40;19&#37;&#41; ou DAP &#40;13&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Idade m&#233;dia &#40;anos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetes &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elegibilidade &#8211; L&#237;pidos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#62;&#61;70 ou c&#8208;n&#227;oHDL &#62;&#61;100 ou ApoB &#62;&#61;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#62;&#61;70 ou c&#8208;n&#227;oHDL &#62;&#61;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#62;&#61;100 ou c&#8208;n&#227;oHDL&#62;&#61;130&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#62;&#61;70 ou c&#8208;n&#227;oHDL &#62;&#61;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL basal &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL atingido no estudo &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#40;<span class="elsevierStyleItalic">vs&#46;</span> 101 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#40;<span class="elsevierStyleItalic">vs&#46;</span> 100 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#40;<span class="elsevierStyleItalic">vs&#46;</span> 137 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#40;<span class="elsevierStyleItalic">vs&#46;</span> 86 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Estatina em dose intensiva &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dura&#231;&#227;o do estudo &#40;anos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resultado Prim&#225;rio &#40;HR e IC 95&#37;&#41; &#47; NNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85&#40;0&#44;78&#8208;0&#44;93&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>NNT&#58; 63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;99 &#40;0&#44;80&#8208;1&#44;22&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;79 &#40;0&#44;65&#8208;0&#44;97&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;85&#40;0&#44;79&#8208;0&#44;92&#41;&#176;NNT&#58; 67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte CV&#44; EM ou AVC &#40;HR e IC 95&#37;&#41; &#47; NNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86&#40;0&#44;79&#8208;0&#44;93&#41;&#176;&#176;NNT&#58; 63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;03 &#40;0&#44;82&#8208;1&#44;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;74 &#40;0&#44;60&#8208;0&#44;92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;80 &#40;0&#44;73&#8208;0&#44;88&#41; NNT&#58; 67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morte CV &#40;HR e IC 95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;88&#40;0&#44;74&#8208;1&#44;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;20 &#40;0&#44;74&#8208;1&#44;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;82 &#40;0&#44;50&#8208;1&#44;36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;05 &#40;0&#44;88&#8208;1&#44;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EM &#40;HR e IC 95&#37;&#41; &#47; NNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;86 &#40;0&#44;77&#8208;0&#44;96&#41;<span class="elsevierStyleSup">X</span> NNT&#58; 100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">RUTHERFORD &#8208;2<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">52</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">HFHe&#40;12 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">140<span class="elsevierStyleHsp" style=""></span>mg 2&#47;2 sem&#58; &#8208; 31&#44;6&#37; 420<span class="elsevierStyleHsp" style=""></span>mg 4&#47;4 sem&#58; &#8208; 28&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TESLA parte A<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">53</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#47;4 sem&#58; &#8208; 16&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#47;4 sem&#58; &#8208; 11&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;2 sem&#58; &#8208; 13&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;2 sem&#58; &#8208; 18&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TESLA parte B<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">44</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHo&#40;12 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 30&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 11&#44;8&#37; &#40;p&#61;0&#44;09&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TAUSSIG<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">54</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HF grave&#40;5 anos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em curso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Estudos com Alirocumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY FH I e FH II<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">55</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHe&#40;78 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FH I&#58; &#8208; 57&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FH I&#58; &#8208; 17&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FH II&#58; &#8208; 51&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FH II&#58; &#8208; 20&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY HIGH<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">56</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHe&#40;78 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 39&#44;1&#37; &#224; sem 24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 14&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY LONG TERM<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">57</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HFHe&#40;78 sem&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8208; 61&#44;9&#37; &#224; sem 24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8208; 25&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ODYSSEY OLE<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Alirocumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Bococizumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Evolocumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Evento adverso&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">77&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">63&#44;7&#37;<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">60&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">77&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">77&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Evento adverso grave&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">24&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Rea&#231;&#227;o local inje&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#44;8&#37;<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">10&#44;4&#37;<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">1&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">2&#44;1&#37;<a class="elsevierStyleCrossRef" href="#tblfn0015">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetes <span class="elsevierStyleItalic">mellitus</span> de novo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#44;2&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">8&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evento neurocognitivo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">1&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Eleva&#231;&#227;o ALT&#40;&#62;3x&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eleva&#231;&#227;o CK<a class="elsevierStyleCrossRef" href="#tblfn0020">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpo neutralizante do inibidor PCSK9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Seguran&#231;a dos AM anti&#8208;PCSK9 nos estudos de eventos CV</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Perfil de doente em preven&#231;&#227;o secund&#225;ria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Limiar de c&#8208;LDL para ser considerada introdu&#231;&#227;o IPCSK9<a class="elsevierStyleCrossRef" href="#tblfn0025">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Recomenda&#231;&#245;es NICE<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">73</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evento cardiovascular pr&#233;vio&#40;SCA&#44; AVC isqu&#233;mico&#44; revasculariza&#231;&#227;o coron&#225;ria ou arterial&#44; doen&#231;a coron&#225;ria ou doen&#231;a arterial perif&#233;rica&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 150 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a polivascularouEventos CV recorrentes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">c&#8208;LDL &#8805;130 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recomenda&#231;&#245;es Sociedade Espanhola Cardiologia<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">74</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SCA &#60; 12 meses &#43; Dislipidemia familiar&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 70 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a coron&#225;ria est&#225;vel ou SCA pr&#233;vio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 100 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SCA recorrente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 70 mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a coron&#225;ria &#43; intoler&#226;ncia&#47;contra&#8208;indica&#231;&#227;o estatinas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Conforme o valor alvo de c&#8208;LDL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recomenda&#231;&#245;es ESC&#47;ESA<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">75</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a cardiovascular cl&#237;nica&#40;SCA&#44; doen&#231;a arterial perif&#233;rica&#44; AVC pr&#233;vios&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805;140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a cardiovascular cl&#237;nica &#43; 1 dos seguintes&#58;&#8208;Dislipidemia Familiar&#8208;Diabetes com LOA ou um fator risco <span class="elsevierStyleItalic">major</span>&#8208;Doen&#231;a cardiovascular grave ou extensa &#40;p&#46;e&#46; polivascular&#41;&#8208;R&#225;pida progress&#227;o DCV &#40;recorr&#234;ncia de SCA&#44; revasculariza&#231;&#227;o coron&#225;ria repetida ou AVC isqu&#233;mico recorrente&#44; nos primeiros 5 anos ap&#243;s um primeiro evento&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208;LDL &#8805; 100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Recomenda&#231;&#245;es ACC&#47;AHA<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">76</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a ateroscler&#243;tica estabelecida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#8208; LDL &#8805; 70<a class="elsevierStyleCrossRef" href="#tblfn0030">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Low&#8208;density lipoproteins cause atherosclerotic cardiovascular disease&#46; 1&#46; Evidence from genetic&#44; epidemiologic&#44; and clinical studies&#46; A consensus statement from the European Atherosclerosis Society Consensus Panel"
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                      "doi" => "10.1093/eurheartj/ehx144"
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                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2017"
                        "volumen" => "38"
                        "paginaInicial" => "2459"
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                          "etal" => true
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                      "doi" => "10.1001/jama.2016.13985"
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                      "titulo" => "2016 ESC&#47;EAS Guidelines for the Management of Dyslipidaemias"
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                      "doi" => "10.1093/eurheartj/ehw272"
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                0 => array:2 [
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                      "titulo" => "2016 European Guidelines on cardiovascular disease prevention in clinical practice&#58; The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice &#40;constituted by representatives of 10 societies and by invited experts&#41;Developed with the special contribution of the European Association for Cardiovascular Prevention &#38; Rehabilitation &#40;EACPR&#41;"
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                          "autores" => array:1 [
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                      "doi" => "10.1093/eurheartj/ehw106"
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                      "titulo" => "American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease"
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Informação do artigo
ISSN: 08702551
Idioma original: Português
DOI:10.1016/j.repc.2019.05.005
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